BACKBONE MODIFIED OLIGONUCLEOTIDE ANALOGS AND SOLID PHASE SYNTHESIS THEREOF

Abstract: Compounds and methods for preparing oligonucleotide analogs are provided. In preferred embodiments, the methods involve solid-phase coupling of synthons bearing either 3'-electrophilic groups and 5'-nucleophilic groups or 5'-electrophilic groups and 3'-nucleophilic groups to form neutral, achiral oligomers.

Description: BACKBONE MODIFIED OLIGONUCLEOTIDE ANALOGS AND SOLID PHASE SYNTHESIS THEREOF CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of U.S. Serial No. 08/174,379, filed December 28, 1993, which is a continuation-in-part of U.S. Serial No. 08/040,903, filed March 31, 1991, which is a continuation-in-part of PCT/US92/04294, filed May 21, 1992, and of U.S. Serial No. 903,160, filed June 24, 1992, which are continuations-in-part of U.S. Serial No. 703,619 filed May 21, 1991, which is a continuation-in-part of U.S. Serial No. 566,836 filed on August 13, 1990 and U.S. Serial No. 558,663 filed on July 27, 1990. This application also is related to the subject matter disclosed and claimed in the following patent applications filed herewith by the present inventors: U.S. Serial No. 08/39,979, filed March 30, 1993; U.S. Serial No. 08/40,526, filed March 31, 1993; and U.S. Serial No. 08/40,933, filed March 31, 1993. Each of these patent applications are assigned to the assignee of this application and are incorporated by reference herein. FIELD OF THE INVENTION This invention relates to the synthesis of nuclease resistant oligonucleotide analogs which are useful for therapeutics, diagnostics and as research reagents. In particular, the invention relates to solid-phase synthetic methods wherein amine-terminated synthons are coupled with aldehyde-terminated synthons to produce hydroxylamino- containing and/or hydrazino-containing covalent linkages. BACKGROUND OF THE INVENTION It is well known that most of the bodily states in mammals, including most disease states, are effected by proteins. Proteins, either acting directly or through their enzymatic functions, contribute in major proportion to many diseases in animals and man. Classical therapeutics generally has focused upon interactions with proteins in an effort to moderate their disease causing or disease potentiating functions. Recently, however, attempts have been made to moderate the production of proteins by interactions with the molecules (i.e., intracellular RNA) that direct their synthesis. These interactions have involved hybridization of complementary "antisense" oligonucleotides or certain analogs thereof to RNA. Hybridization is the sequence-specific hydrogen bonding of oligonucleotides or oligonucleotide analogs to RNA or to single stranded DNA. By interfering with the production of proteins, it has been hoped to effect therapeutic results with maximum effect and minimal side effects. The pharmacological activity of antisense oligonucleotides and oligonucleotide analogs, like other therapeutics, depends on a number of factors that influence the effective concentration of these agents at specific intracellular targets. One important factor for oligonucleotides is the stability of the species in the presence of nucleases. It is unlikely that unmodified oligonucleotides will be useful therapeutic agents because they are rapidly degraded by nucleases. Modification of oligonucleotides to render them resistant to nucleases therefore is greatly desired. Modification of oligonucleotides to enhance nuclease resistance generally has taken place on the phosphorus atom of the sugar-phosphate backbone. Phosphorothioates, methyl phosphonates, phosphoramidates and phosphorotriesters have been reported to confer various levels of nuclease resistance. Phosphate-modified oligonucleotides, however, generally have suffered from inferior hybridization properties. See, e . g. , Cohen, J.S., ed. Oligonucleotides : Antisense Inhibi tors of Gene Expression, (CRC Press, Inc., Boca Raton FL, 1989) . Another key factor is the ability of antisense compounds to traverse the plasma membrane of specific cells involved in the disease process. Cellular membranes consist of lipid-protein bilayers that are freely permeable to small, nonionic, lipophilic compounds and are inherently impermeable to most natural metabolites and therapeutic agents. See, e . g. , Wilson, Ann . Rev. Biochem . 1978, 47, 933. The biological and antiviral effects of natural and modified oligonucleotides in cultured mammalian cells have been well documented. It appears that these agents can penetrate membranes to reach their intracellular targets. Uptake of antisense compounds into a variety of mammalian cells, including HL-60, Syrian Hamster fibroblast, U937, L929, CV-1 and ATH8 cells has been studied using natural oligonucleotides and certain nuclease resistant analogs, such as alkyl triesters and methyl phosphonates. See, e . g. , Miller, et al . , Biochemistry 1977, 16, 1988; Marcus-Sekura, et al . , Nucleic Acids Research 1987, 15, 5749; and Loke, et al . , Top. Microbiol . Immunol . 1988, 141 , 282. Often, modified oligonucleotides and oligonucleotide analogs are internalized less readily than their natural counterparts. As a result, the activity of many previously available antisense oligonucleotides has not been sufficient for practical therapeutic, research or diagnostic purposes. Two other serious deficiencies of prior art compounds designed for antisense therapeutics are inferior hybridization to intracellular RNA and the lack of a defined chemical or enzyme-mediated event to terminate essential RNA functions. Modifications to enhance the effectiveness of the antisense oligonucleotides and overcome these problems have taken many forms. These modifications include base ring modifications, sugar moiety modifications and sugar-phosphate backbone modifications. Prior sugar-phosphate backbone modifications, particularly on the phosphorus atom, have effected various levels of resistance to nucleases. However, while the ability of an antisense oligonucleotide to bind to specific DNA or RNA with fidelity is fundamental to antisense methodology, modified phosphorus oligonucleotides have generally suffered from inferior hybridization properties. Replacement of the phosphorus atom has been an alternative approach in attempting to avoid the problems associated with modification on the pro-chiral phosphate moiety. For example, Matteucci, Tetrahedron Letters 1990, 31 , 2385 disclosed the replacement of the phosphorus atom with a methylene group. However, this replacement yielded unstable compounds with nonuniform insertion of formacetal linkages throughout their backbones. Cormier, et al . , Nucleic Acids Research 1988, 16, 4583, disclosed replacement of phosphorus with a diisopropylsilyl moiety to yield homopolymers having poor solubility and hybridization properties. Stirchak, et al . , Journal of Organic Chemistry 1987, 52, 4202 disclosed replacement of phosphorus linkages by short homopolymers containing carbamate or morpholino linkages to yield compounds having poor solubility and hybridization properties. Mazur, et al . , Tetrahedron 1984, 40, 3949, disclosed replacement of a phosphorus linkage with a phosphonic linkage yielded only a homotrimer molecule. Goodchild, Bioconjugate Chemistry 1990, 1, 165, disclosed ester linkages that are enzymatically degraded by esterases and, therefore, are not suitable for antisense applications. The limitations of available methods for modification of the phosphorus backbone have led to a continuing and long felt need for other modifications which provide resistance to nucleases and satisfactory hybridization properties for antisense oligonucleotide diagnostics and therapeutics. OBJECTS OF THE INVENTION It is an object of the invention to provide oligonucleotide analogs for diagnostic, research, and therapeutic use. It is a further object of the invention to provide oligonucleotide analogs capable of forming duplex or triplex structures. It is a further object of the invention to provide oligonucleotide analogs having enhanced cellular uptake. Another object of the invention is to provide oligonucleotide analogs having greater efficacy than unmodified antisense oligonucleotides. It is yet another object of the invention to provide methods for synthesis and use of oligonucleotide analogs. These and other objects will become apparent to persons of ordinary skill in the art from a review of the present specification and the appended claims. SUMMARY OF THE INVENTION The present invention provides novel compounds that mimic and/or modulate the activity of wild-type nucleic acids. In general, the compounds contain a selected nucleoside sequence which is specifically hybridizable with a targeted nucleoside sequence of single stranded or double stranded DNA or RNA. At least a portion of the compounds of the invention has structure I : wherein: L 1 -L 2 -L 3 -L 4 is CHa-R A -NRi-CHa, CHa-NR^ A -CHa, R A -NR^ CH 2 -CH 2 , CHa-CHa- Ri-R A , CHa-CHa-R A -NR^ or NR^ A -CHa-CHa,- R A is 0 or NR 2 ; each R x and R 2 are, independently, the same or different and are H; alkyl or substituted alkyl having 1 to about 10 carbon atoms; alkenyl or substituted alkenyl having 2 to about 10 carbon atoms; alkynyl or substituted alkynyl having 2 to about 10 carbon atoms; alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl having 7 to about 14 carbon atoms; alicyclic; heterocyclic; a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an • ■ oligonucleotide; B x is a nucleosidic base; n is an integer greater than 0; Q is 0, S, CH 2 , CHF or CF 2 ; X is H; OH; alkyl or substituted alkyl having 1 to about 10 carbon atoms; alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl having 7 to about 14 carbon atoms; F; Cl; Br; CN; CF 3 ; 0CF 3 ; OCN; 0-alkyl; S-alkyl; N-alkyl; O- alkenyl; S-alkenyl; N-alkenyl; S0CH 3 ; S0 2 CH 3 ; 0N0 2 ; N0 2 ; N 3 ; NH 2 ; heterocycloalkyl; heterocycloalkaryl; aminoalkylamino; polyalkylamino or substituted silyl; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide. The compounds of the invention are prepared by coupling preselected 3' -functionalized and 4' -functionalized nucleosides and/or oligonucleotides under conditions effective to form the above-noted L 1 -L 2 -L 3 -L 4 linkages. In certain embodiments, a 3'-C-formyl nucleoside or oligonucleotide synthon is reacted with a support-bound 5'- hydroxylamino or 5'-hydrazino nucleoside or oligonucleotide synthon. In other embodiments, a 4'-C-formyl synthon is reacted with a support-bound 3' -methylhydroxylamino or 3' - methylhydrazino synthon. In still further embodiments, linkages having structure CH=N-R A -CH 2 , CH 2 -CH=N-R A , CH 2 -R A - N=CH, or R A -N=CH-CH 2 where R A is 0 or NR- L are formed by coupling synthons having structures II and III: II wherein: Z- L and Y 2 are selected such that (i) Zj is C(0)H and Y 2 is CH 2 R A NH 2 ; or (ii) Z ± is CH 2 R A NH 2 and Y 2 is C(0)H; or (iii) Z is CH 2 C(0)H and Y 2 is R A NH 2 ; or (iv) Z x is R A NH 2 and Y 2 is H(0)CCH 2 ; Y 1 is OH, 0R HP , CH 2 OH, or CH 2 OR HP where R HP is a hydroxyl protecting group; (P) is a solid support; each L c is, independently, a covalent linkage having structure CH=N-R A -CH 2 , CH 2 -CH=N-R A , CH 2 -R A -N=CH, R A -N=CH-CH 2 ; CH 2 -NH-R A -CH 2 , CH 2 -CH 2 -NH-R A , CH 2 -R A -NH-CH 2 , R A -NH-CH 2 -CH 2 , 0- P(0) 2 0-CH 2 , or O-P(S) (0)0-CH 2 ; and n is 0-200. BRIEF DESCRIPTION OF THE DRAWINGS The numerous objects and advantages of the present invention may be better understood by those skilled in the art by reference to the accompanying figures, in which: Figures 1 and 2 show exemplary compounds used in accordance with the invention. Figure 3 is a synthetic scheme depicting a preferred method for preparation of oxime-linked oligonucleotide analogs. DETAILED DESCRIPTION OF THE INVENTION The term "nucleoside" as used in connection with this invention refers to a unit made up of a heterocyclic base and its sugar. The term "nucleotide" refers to a nucleoside having a phosphate group on its 3' or 5 ' sugar hydroxyl group. Thus nucleosides, unlike nucleotides, have no phosphate group. "Oligonucleotide" refers to a plurality of joined nucleotide units formed in a specific sequence from naturally occurring bases and pentofuranosyl groups joined through a sugar group by native phosphodiester bonds. This term refers to both naturally occurring and synthetic species formed from naturally occurring subunits. The compounds of the invention generally can be viewed as "oligonucleotide analogs", that is, compounds which function like oligonucleotides but which have non-naturally occurring portions. Oligonucleotide analogs can have altered sugar moieties, altered base moieties or altered inter-sugar linkages. For the purposes of this invention, an oligonucleotide analog having non-phosphodiester bonds, i.e., an altered inter-sugar linkage, is considered to be an "oligonucleoside. " The term "oligonucleoside" thus refers to a plurality of nucleoside units joined by linking groups other than native phosphodiester linking groups. The term "oligomers" is intended to encompass oligonucleotides, oligonucleotide analogs or oligonucleosides. Thus, in speaking of "oligomers" reference is made to a series of nucleosides or nucleoside analogs that are joined via either natural phosphodiester bonds or other linkages, including the four atom linkers of this invention. Although the linkage generally is from the 3' carbon of one nucleoside to the 5' carbon of a second nucleoside, the term "oligomer" can also include other linkages such as 2' -5' linkages. Oligonucleotide analogs also can include other modifications consistent with the spirit of this invention, particularly modifications that increase nuclease resistance. For example, when the sugar portion of a nucleoside or nucleotide is replaced by a carbocyclic moiety, it is no longer a sugar. Moreover, when other substitutions, such a substitution for the inter-sugar phosphorodiester linkage are made, the resulting material is no longer a true nucleic acid species. All such compounds are considered to be analogs. Throughout this specification, reference to the sugar portion of a nucleic acid species shall be understood to refer to either a true sugar or to a species taking the structural place of the sugar of wild type nucleic acids. Moreover, reference to inter-sugar linkages shall be taken to include moieties serving to join the sugar or sugar analog portions in the fashion of wild type nucleic acids. This invention concerns modified oligonucleotides, i.e., oligonucleotide analogs or oligonucleosides, and methods for effecting the modifications. These modified oligonucleotides and oligonucleotide analogs exhibit increased chemical and/or enzymatic stability relative to their naturally occurring counterparts. Extracellular and intracellular nucleases generally do not recognize and therefore do not bind to the backbone-modified compounds of the invention. In addition, the neutral or positively charged backbones of the present invention can be taken into cells by simple passive transport rather than by complicated protein-mediated processes. Another advantage of the invention is that the lack of a negatively charged backbone facilitates sequence specific binding of the oligonucleotide analogs or oligonucleosides to targeted RNA, which has a negatively charged backbone and will repel similarly charged oligonucleotides. Still another advantage of the present invention is it presents sites for attaching functional groups that initiate cleavage of targeted RNA. The modified internucleoside linkages of this invention are intended to replace naturally-occurring phosphodiester-5' -methylene linkages with four atom linking groups to confer nuclease resistance and enhanced cellular uptake to the resulting compound. Preferred linkages have structure CHa-R A -NRi-CHa, CE 2 -NR 1 -R h -CU 2 , R A -NR^C^-C^, CH 2 -CH 2 - NR^R A , CHz-CHa-R A -NRi, or NR^ A -CHa-CHa where R A is 0 or NR 2 . Generally, these linkages are prepared by functionalizing the sugar moieties of two nucleosides which ultimately are to be adjacent to one another in the selected sequence. In a 4' to 3' sense, an "upstream" synthon such as structure III is modified at its terminal 3' site, while a "downstream" synthon such as structure II is modified at its terminal 4' site. More specifically, the invention provides efficient syntheses of oligonucleosides via intermolecular reductive coupling on a solid support. B x can be nucleosidic bases selected from adenine, guanine, uracil, thymine, cytosine, 2-aminoadenosine or 5- methylcytosine, although other non-naturally occurring species can be employed to provide stable duplex or triplex formation with, for example, DNA. Representative bases are disclosed in U.S. Patent No. 3,687,808 (Merigan, et al . ) , which is incorporated herein by reference. Q can be S, CH 2 , CHF CF 2 or, preferably, 0. See, e . g. , Bellon, et al . , Nucleic Acids Res . 1993, 21 , 1587. X can be H, OH, alkyl, substituted alkyl, alkaryl or aralkyl, F, Cl, Br, CN, CF 3 , 0CF 3 , OCN, O-alkyl, S-alkyl, N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, SOCH 3 , S0 2 CH 3 , ON0 2 , N0 2 , N 3 , NH 2 , heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino or substituted silyl, an RNA cleaving group, a group for improving the pharmacokinetic properties of an oligonucleotide, or a group for improving the pharmacodynamic properties of an oligonucleotide. It is intended that the term "alkyl" denote branched and straight chain hydrocarbyl residues, including alkyl groups having one or more 3 H and/or 1 C atoms. It is preferred that X is H or OH, or, alternatively F, O-alkyl or O-alkenyl, especially where Q is 0. Preferred alkyl and alkenyl groups have from 1 to about 10 carbon atoms. Solid supports ( e . g. , (P) ) according to the invention include any of those known in the art for polynucleotide synthesis, including controlled pore glass (CPG) , oxalyl-controlled pore glass ( see, e . g. , Alul, et al . , Nucleic Acids Research 1991, 19, 1527) , TentaGel Support -- an aminopolyethyleneglycol derivatized support ( see, e . g. , Wright, et al . , Tetrahedron Letters 1993, 34 , 3373) or Poros -- a copolymer of polystyrene/divinylbenzene. Attachment and cleavage of nucleosides and oligonucleosides can be effected via standard procedures. See, e . g. , Pon, R.T. in Protocols for Oligonucleotides and Analogs, Agrawal, S., ed. , Humana Press, Totowa, NJ, 1993. As used herein, the term solid support further includes any linkers ( e . g. , long chain alkyl amines and succinyl residues) used to bind a growing oligonucleoside to a stationary phase such as CPG. Y can be OH, OR HP , CH 2 0H, or CH 2 0R HP where R HP is a hydroxyl protecting group. A wide variety of hydroxyl protecting groups can be employed in the methods of the invention. See, e . g. , Beaucage, et al . , Tetrahedron 1992, 12 , 2223. In general, protecting groups render chemical functionality inert to specific reaction conditions, and can be appended to and removed from such functionality in a molecule without substantially damaging the remainder of the molecule. Representative hydroxyl protecting groups include phthalimido, t-butyldimethylsilyl (TBDMS) , t- butyldiphenylsilyl (TBDPS) , fluorenylmethoxycarbonyl (FMOC) , and other hydroxyl protecting groups. It is preferred that the oligonucleotide analogs of the invention comprise from about 5 to about 50 subunits having the given structure (i.e., n = 5-50) . While each subunit of the oligonucleotide analogs can have repetitive structure I, such need not be the case. For example, the subunits can have alternating or more random structures. The invention is also directed to methods for the preparation of oligonucleosides with modified inter-sugar linkages. These modifications may be effected using solid supports which may be manually manipulated or used in conjunction with a DNA synthesizer using methodology commonly known to those skilled in DNA synthesizer arts . Generally, the procedure involves functionalizing the sugar moieties of two nucleosides which will be adjacent to one another in the selected sequence. In a 5' to 3' sense, an "upstream" synthon such as structure II is modified at its terminal 3' site, while a "downstream" synthon such as structure III is modified at its terminal 5' site. More specifically, certain linkages can be formed by selecting a 3'-C-formyl derivatized compound as the upstream synthon and a 5' -aminohydroxy derivatized compound as the downstream synthon. Coupling then is effected to provide, for example, a dinucleoside having an oxime linkage. In this instance, the oxime is present as E/Z isomers. The oxime nitrogen atom is adjacent to a carbon atom on the 3' end of the upstream nucleoside. Dinucleosides having the oxime nitrogen adjacent to a carbon atom on the 5' or downstream nucleoside are synthesized utilizing a 4'-C-formyl derivatized compound as the upstream synthon and a 3'-deoxy- 3' -aminohydroxymethyl derivatized compound as the downstream synthon, again providing E/Z isomers. In both instances the oxime linked compound can be incorporated directly into an oligomer and/or can be reduced to a corresponding hydroxylamino linked species. Reduction of oxime linked dinucleosides either as the dinucleoside or as a dinucleoside moiety in an oligomer with sodium cyanoborohydride yields the corresponding hydroxylamino linked compounds. Hydroxylamino linked compounds can be alkylated at the amino moiety of the hydroxylamino linkage to yield a corresponding N-alkylamino linkage. 3'-C-fσrmyl derivatized nucleosides can be formed via several synthetic pathways. The presently preferred method utilizes a stereoselective intermolecular radical C-C bond formation reaction, ( see, e . g. , U.S. Application Serial No. 08/040,903, filed March 31, 1993) . Thus, a 3'-0- phenylthiocarbonate ester derivative of thymidine reacted with jβ-tri-n-butylstannylstyrene and AIBN to provide a 3'-C- styryl derivative, which on oxidative cleavage gave a 3'-C- formyl thymidine derivative. In a similar manner, a radical carbonylation of the corresponding 3 ' -deoxy-3 ' -iodo nucleoside gives the 3'-C-formyl nucleotide analog. The iodo compound is treated with CO, 2,2' -azobisisobutrylonitrile (AIBN) , and tris (trimethylsilyl) silane (TTMS) . Alternately, 3'-C-formyl derivatized compounds can be synthesized from either a 3' -deoxy-3' -cyano sugar or nucleoside. Both 4'-C- formyl (also identified as 5'-aldehydo) and 3'-C-formyl group can be blocked in a facile manner utilizing O- methylaminobenzenthiol as a blocking group. The 4'- and 3'- C-formyl groups can be deblocked with silver nitrate oxidation. An alternate method of 3'-C-formyl nucleoside synthesis employs l-O-methyl-3' -deoxy-3' -O-methylaminobenzene thiol-5' -O-trityl-S-D-erythro-pento furanoside, which serves as a precursor for any 3' -deoxy-3' -C-formyl nucleoside. The l-O-methyl-3 ' -deoxy-3' -O-methyl amino benzenethiol-5' -O- trityl-β-D-erythro-pentofuranoside is reacted with an appropriate base utilizing standard glycosylation conditions and then deblocked to yield the nucleoside. In yet another method, a 3' -deoxy-3' -cyano nucleoside is prepared from either the corresponding 3' -deoxy-3' -iodo nucleoside or by glycosylation with l-O-methyl-3' -deoxy-3' -O-cyano-5' -0- trityl-β-D-ervthro-pentofuranoside. Oligonucleosides according to the invention, linked by hydrazines, hydroxylamines and other linking groups, can be protected by a dimethoxytrityl group at the 5' -hydroxyl and activated for coupling at the 3'-hydroxyl with cyanoethyldiisopropyl-phosphite moieties. These compounds can be inserted into any desired sequence by standard, solid phase, automated DNA synthesis techniques. One of the most popular processes is the phosphoramidite technique ( see, e . g. , Beaucage, et al. , Tetrahedron 1992, 48, 2223 and references cited therein) , wherein a nucleoside or oligonucleotide having a free hydroxyl group is reacted with a protected 2' -cyanoethyl phosphoramidite monomer or oligomer in the presence of a weak acid to form a phosphite-linked structure. Oxidation of the phosphite linkage followed by hydrolysis of the cyanoethyl group yields the desired phosphate or phosphorothioate linkage. In one embodiment of the invention, protected oligonucleosides are linked with the units of a specified DNA sequence utilizing normal phosphodiester bonds. The resulting oligonucleotide analog or oligomer has a "mixed" backbone containing both phosphodiester linkages and four atom linkages of the inventions. In this manner, a sequence-specific 15-mer oligonucleotide can be synthesized to have seven hydroxylamine, hydrazine or other type linked dinucleosides attached via alternating phosphodiester linkages. Such a structure will provide increased solubility in water compared to fully modified oligomers, which may contain linkages of the invention. Oligonucleosides containing a uniform backbone linkage can be synthesized by use of CPG-solid support and standard nucleic acid synthesizing machines such as Applied Biosystems Inc. 380B and 394 and Milligen/Biosearch 7500 and 8800s. The initial nucleoside (number 1 at the 3 '-terminus) is attached to a solid support such as controlled pore glass . In sequence specific order, each new nucleoside is attached either by manual manipulation or by the automated synthesizer system. One preferred method, shown in Figure 1, employs a solid support to which has been bound a downstream synthon having a protected 5' site. The 5' site preferably is protected with a phthalimido group. This permits the extent of nucleoside loading on the support to be determined by UV/visible spectrophotometry, as treatment with 3% N- methylhydrazine in methylene chloride yields 1,2-dihydro-4- hydroxy-2-methyl-l-oxaphthalazine (DHMO) , which has λ max = 304 nm and e= 6,000 1 cm "1 mol "1 . In addition, emission spectroscopy has been utilized to determine the percent deblocking of the 5' -O-phthalimido group by measuring the release of DHMO. ( see, e . g. , Example 11). The 5' site of the downstream synthon can be liberated with any nucleophilic base having a pKa from about 7.7 to about 10.0. The selected base should not appreciably react with any linker used to bind a growing oligonucleoside to a stationary phase. Representative bases include hydrazine and methylhydrazine. The 5' site preferably is liberated with 3% methylhydrazine in methylene chloride and washed with methylene chloride:methanol. The aminohydroxyl group at the 5' position of the upstream synthon also is protected with a phthalimido group to yield a 5' -phthalimido protected 3'- deoxy-3' -C-formyl nucleoside, which is reacted with the downstream synthon in, for example, 2.5% acetic acid in methylene chloride. Deprotection at the 5' position and washing liberates the next 5' -aminohydroxy reaction site. The cycle is repeated with the further addition of upstream synthon until the desired sequence is constructed. Each nucleoside of this sequence is connected with oxime linkages. The terminal nucleoside of the desired oligonucleoside preferably is added to the sequence as a 5'-OTBDMS blocked 3' -deoxy-3' -C-formyl nucleoside. The oxime linked oligonucleoside can be removed from the support with, for example, ammonium hydroxide. If an aminohydroxyl linked oligonucleoside is desired, the oxime linkages are reduced with sodium cyanoborohydride in acetic acid. Alternately reduction can be accomplished while the oxime linked oligonucleoside is still attached to the support. Free amino groups produced upon reduction can be alkylated with, for example, acetone and sodium cyanoborohydride in acetic acid. The alkylation step can be used to introduce other, useful, functional molecules on the macromolecule. Such useful functional molecules include but are not limited to reporter molecules, RNA cleaving groups, groups for improving the pharmacokinetic properties of an oligonucleotide, and groups for improving the pharmacodynamic properties of an oligonucleotide. Such molecules can be attached to or conjugated to the macromolecule via attachment to the nitrogen atom in the backbone linkage. Alternatively, such molecules can be attached to pendent groups extending from the 2' position of the sugar moiety of one or more of the nucleosides of the macromolecules. Examples of such other useful functional groups are provided by United States patent application serial number 782,374, filed Oct. 24, 1991, entitled Derivatized Oligonucleotides Having Improved Uptake & Other Properties, assigned to the same assignee as this application, herein incorporated by reference, and in other of the above-referenced patent applications. In certain preferred compounds of the invention, pendent groups extending from the 2' position enhance binding or hybridization of the compound to a target nucleic acid. Dimeric pairs of compounds of the invention linked via MMI [methylene (methylimino) ] linkages were studies by NMR. While we do not wish to be bound by theory, the sugar moieties of RNA and DNA oligonucleotides normally are located in one of two major conformations, either the C2'-endo conformation (DNA like or southern conformation) or the C3'-endo conformation (RNA like or northern conformation) . While other conformations are possible, such as 04-endo, generally the greatest percentage of the sugar moieties of the nucleoside molecules will be in one or the other of the C3' - endo or C2'-endo conformation. In this study the two sugar moieties, the 3' sugar and the 5' sugar, in a dimer pair were analyzed as to the percentage of the sugar moiety located in either the C2'-endo conformation (DNA like or southern conformation) or the C3'-endo conformation (RNA like or northern conformation) . Again while we do not wish to be bound by theory, it has generally been found that for binding to RNA, the C3'-endo conformation is preferred since, in identical sequences, RNA-RNA binding is generally stronger than RNA-DNA binding which in turn is stronger than DNA-DNA binding. In this study, for T-T dimers linked by normal phosphodiester linkages 35% of the 5' sugar and 28% of the 3' sugar were determined by NMR to be in the C3'-endo conformation. Thus for the phosphodiester linkage, both of the 3' and the 5' sugar are very DNA like, existing in the C2'-endo conformation. In contrast, in a T-T dimer linked by MMI linkages of the invention, 68% of the 5' sugar and 31% of the 3' sugar were determined to be in the C3'-endo conformation. Again while we do not wish to be bound by theory, this increase in RNA character imparted by the MMI linkage might contribute to the +0.2 °C increase in Tm per modification for MMI oligomers as compared to normal phosphodiester oligonucleotides. When we substituted a 2'-0- methyl modified sugar for the 3' deoxy sugar in our MMI linked T-T dimers further RNA like characteristic were imparted to the dimers. Now 66% of the 5' sugar was in the C3'-endo conformation while 65% of the 3' sugar of the T-T 2 , .0. methyl dimer pair resided in the C3'-endo conformation. When a 2'-0-fluoro modified sugar was substituted for the 3' deoxy sugar of our MMI T-T dimer pair, the percent of C3'-endo for the 3' sugar increased to 92% while the 5' sugar increased to 70%. Thus in the T-T 2 ,. p dimer pair, the 2'-modified sugar imparted even greater RNA like characteristics even though neither sugar moiety contained a RNA 2'-hydroxyl group. These increasing RNA like characteristics are reflected in increased hybridization as illustrated by their Tms shown in Tables 3 and 4 of the Examples of this specification. The compounds of this invention can be used in diagnostics, therapeutics, and as research reagents and kits. For therapeutic use the oligonucleotide analog is administered to an animal suffering from a disease modulated by some protein. It is preferred to administer to patients suspected of suffering from such a disease an amount of oligonucleotide analog that is effective to reduce the symptomology of that disease. One skilled in the art can determine optimum dosages and treatment schedules for such treatment regimens . It is preferred that the RNA or DNA portion which is to be modulated be preselected to comprise that portion of DNA or RNA which codes for the protein whose formation or activity is to be modulated. The targeting portion of the composition to be employed is, thus, selected to be complementary to the preselected portion of DNA or RNA, that is to be an antisense oligonucleotide for that portion. In accordance with one preferred embodiment of this invention, the compounds of the invention hybridize to HIV mRNA encoding the tat protein, or to the TAR region of HIV mRNA. In another preferred embodiment, the compounds mimic the secondary structure of the TAR region of HIV mRNA, and by doing so bind the tat protein. Other preferred compounds complementary sequences for herpes, papilloma and other viruses . It is generally preferred to administer the therapeutic agents in accordance with this invention internally such as orally, intravenously, or intramuscularly. Other forms of administration, such as transdermally, topically, or intralesionally may also be useful. Inclusion in suppositories may also be useful. Use of pharmacologically acceptable carriers is also preferred for some embodiments . This invention is also directed to methods for the selective binding of RNA for research and diagnostic purposes. Such selective, strong binding is accomplished by interacting such RNA or DNA with compositions of the invention which are resistant to degradative nucleases and which hybridize more strongly and with greater fidelity than known oligonucleotides or oligonucleotide analogs. Additional objects, advantages, and novel features of this invention will become apparent to those skilled in the art upon examination of the following examples thereof, which are not intended to be limiting, wherein parts and percents are by weight unless otherwise indicated. EXAMPLE 1 Capping Of Free Amino Group Of Succinyl-CPG, 2 To a suspension of succinyl-CPG [1 , (10.0 g) , . prepared according to the procedure of Damha, et al . , Nucleic Acids Res . 1990, 18, 3813-21] , in glacial acetic acid (50 ml) , 20% formaldehyde in water (1.0 ml) was added. The resulting mixture was shaken for 15 minutes. Sodium cyanoborohydride (180 mg) was added in two portions with 5 minutes shaking between each addition. Addition of 20% formaldehyde in water followed by a double reduction with sodium cyanoborohydride was repeated once. The CPG beads were washed thoroughly with dichloromethane methanol (3 x 50 ml, 1:1, v/v) and cloudy solution was decanted. Finally, CPG beads 2 were filtered off and washed with ethyl ether and dried under vacuum for 6 hours. EXAMPLE 2 CPG Loading A. 5' -O-Phthalimido-3' -O- (succinyl-CPG-NMe 2 ) - thymidine, 8. 5 * -O-Phthalimidothymidine (3 ./ 0.8 mmol.), dimethylaminopyridine (0.2 mmol.) , 2 . (2.0 g) , triethylamine (160μl) and DEC (4.0 mmol.) were shaken together in dry pyridine (24 ml) for 66 hours. Pentachlorophenol (1.0 mmol) was added and the resulting mixture was shaken for 24 hours. The CPG beads were filtered off and washed thoroughly with pyridine (30 ml) , dichloromethane (30 ml) and ether (30 ml) . The CPG beads then were dried under vacuum for 2 hours . Then, the CPG beads were shaken with piperidine (10 ml) for 15 minutes, filtered off and washed with dichloromethane (30 ml) ether (30 ml) and dried under vacuum for 4 hours. The resulting beads were suspended in glacial acetic acid (10 ml) and sonicated for 30 minutes. The suspension was diluted with methanol dichloromethane (3 x 30 ml, 1:1 v/v) and cloudy solution was decanted. Then, the CPG beads were filtered off washed with dichloromethane (30 ml) and ether (30 ml) and dried under vacuum over P 2 0 5 for 12 hours, to yield to 8 . . The loading was 35 μmol of 3 . per gram of CPG. B. 5' -O-Phthalimido-3' -O- (suσcinyl-CPG-NMe 2 ) -2' - deoxyadenosine, 9 . The procedure of Example 2A was repeated except that 5' -O-phthalimido-2' -deoxyadenosine 4 . was used in place of 5' -O-phthalimidothymidine. The loading was 36 μmol of 4 . per gram of CPG. C. 5' -0-Phthalimido-3' -0- (succinyl-CPG-NMe 2 ) -2'- isobutyryl-0-6-diphenylcarbamoyl-2' -deoxyguanosine, 10 The procedure of Example 2A was repeated except that 5' -O-phthalimido-N-2-isobutyryl-) -6-diphenylcarbamoyl- 2' -deoxyguanosine 5 was used in place of 5'-0- phthalimidothymidine. The loading was 38 μmol of 5 . per gram of CPG. D. 5'-0-Phthalimido-3'-0- (succinyl-CPG-NMe 2 ) -N-4- protected-2' -deoxycytidine, 11 The procedure of Example 2A was repeated except that 5' -0-phthalimido-N-4-benzoyl-2' -deoxycytidine 6 . was used in place of 5' -O-phthalimidothymidine. The loading was 32 μmol of 6 . per gram of CPG. E. 5'-0-Phthalimido-3'-0- (succinyl-CPG-NMe 2 ) -5- methyl-N-4-protected-2 / -deoxycytidine, 12 The procedure of Example 2A is repeated except that 5' -0-phthalimido-5-methyl-N-4-benzoyl-2' -deoxycytidine 7 . is used in place of 5' -O-phthalimidothymidine. EXAMPLE 3 Synthesis of Homothymidylate 3' -De(oxyphosphinico) -3' - [methylene(methylimino) ] backbone, T12 MMI A. Step 1. 5' -O-Phthalimidothymidine-3' -O-succinyl-CPG (7 . , 28 mg, lμmol of nucleoside) was packed into a small column and connected on an ABI DNA synthesizer model 380B. Compound 7 . was treated with a solution 3% N-methyl hydrazine in dichloromethane: methanol (9:1 v/v) for 120 seconds with a 300 second wait step to give 5' -0-amino-thymidine-3' -0- succinyl-CPG. B. Step 2. The CPG was washed with dichloromethane for 240 seconds. C. Step 3. 5' -O-Phthalimido-3' -C-aldehydo-3' -deoxythymidine 13 . in a 0.1 M solution of dichloromethane mixed with a 5% glacial acetic acid in dichloromethane (1:1, v/v) was passed through the column for 15 seconds (20 eq.) with a 600 minute wait step. D. Step 4. The CPG was washed with dichloromethane for 150 seconds. E. Step 5. Steps 1-4 were repeated ten times. F. Step 6. The 5-terminal nucleotide, e . g. , 5'-t- butyldiphenylsilyl-3' -aldehyde-3' -deoxy-thymidine 18 . , was incorporated following step 3. The excess of 18 was removed by washing step 4. G. Step 7. The resulting CPG beads (with oligomer) were transferred into a small flask and 1.0 ml of glacial acetic acid was added. NaCNBH 3 (15 mg) was added and the mixture was shaken and sonicated for .15 minutes. Formaldehyde (20% in water, lOOμl) was added, the mixture was sonicated for 15 minutes and NaCNBH 3 (2 x 15mg) was added with 15 minutes sonication between each addition. The resulting beads were washed with methanol dichloromethane (1:1, v/v, 15 ml) . H. Step 8. Oligomer was cleaved from the solid support by treatment with 30% ammonia for 2 hours at room temperature. The ammonia then was evaporated. I . Step 9 . The dried residue was dissolved in tetrahydrofuran (THF) /dioxane (1.0 ml, 1:1 v/v) . Tetrabutylammonium fluoride (TBAF) solution (1.0 M) in THF (40μl) was added and the mixture was stirred for 16 hours. The resulting suspension was diluted with triethyl ammonium acetate (pH 7.0, 500 μl of 50 mM solution) and was concentrated under vacuum. j. Step iθ. Purification of the oligomer of step 9 was effected by HPLC. A reverse phase Supelcosil LC-18 (5 μm, 5.0 x 0.46 cm) column and a precolumn (5 μm, 1.0 x 0.46 cm) were used for purifications. The optimal separation was achieved by elution (1 ml/minute) with ammonium acetate buffer (pH 5.9) mixed with 15% acetonitrile and increasing the polarity with 50% of acetonitrile in 25 minutes. The desired T 12 oligomer was eluted (retention time = 28.8 minutes) with isocratic 1:1 acetonitrile and ammonium acetate. EXAMPLE 4 Synthesis Of Mixed Phosphodiester And MMI Linked Oligomer: 5'-TPT*T*T-3' [p = 3'-0-P(0) 2 -0-5'; . = 3'CH 2 -N (CH 3 )-0-5 / ] CPG-loaded T.T oxime dimer was prepared as described in Example 3. Thus, twice repeating the steps 1-4 provided T.T oxime dimer. This dimer was further extended by repeating steps 1-4 using a 5'0-FMOC (9- fluorenylmethoxycarbonyl) protected nucleoside 22_ instead of nucleoside 12 . during step 3. This modification provides a convenient way of switching to standard phosphoramidite chemistry without removing the CPG from automated DNA synthesizer. The resulting T.T.T oxime trimer, still attached to CPG, was treated with a solution of 5% piperidine in acetonitrile for two minutes with a flow rate of 1.6 ml/minute. A three minute waiting step and a three minute acetonitrile wash step following the piperidine treatment removed the 5'-0-FMOC group completely ( see, e . g. , Ma et al . Biopolymers 1989, 28, 965-993) . The T * T.T oxime trimer bearing a free 5' -OH group now was ready for a standard phosphoramidite cycle of DNA synthesis. Thymidine was incorporated as the last residue utilizing a procedure generally in accordance with Oligonucleotide Synthesis, M.J. Gait, ed., IRL Press, Oxford, 1984, to furnish a tetramer. The two oxime linkages of the tetramer were reduced and methylated following NaCNBH 3 /AcOH/HCHO treatments as described in step 7 of Example 3. The resulting tetramer was cleaved from the CPG following step 8 of Example 3. The crude tetramer was purified by HPLC in a similar protocol as described in step 10 of Example 7. The title compound was eluted (retention time = 26.4 minutes) over 30 minutes with an acetonitrile gradient of 5% to 25% mixed with buffer (triethylammonium acetate, pH 5.9) . The product was further characterized by mass spectra (calculated 1614.57; observed 1614.25) and capillary gel electrophoresis (CE; 10% polyacrylamide, 45 cm X 75 μm capillary, 30 KV/30°C) as clean material (single peak at 5.6 minutes retention time on CE) . EXAMPLE 5 Synthesis Of Mixed Phosphorothioate And MMI Linked Oligomer: 5'-TpsT.T.T-3' [ps = 3' -O-P(O) (S) -0-5' ; * = 3'-CH 2 - N(CH 3 ) -O- 5'] T.T.T oxime trimer was prepared as described in Example 4. The last thymidine nucleoside residue was incorporate utilizing standard phosphoramidite chemistry, followed sulfurization with Beaucage reagent ( see, Beaucage et al . , Tetrahedron 1992, 48, 2223-2312) to provide a CPG attached tetramer. The CPG was taken off the DNA synthesizer and treated in a manner described in steps 7 and 8 of Example 3. The product was purified by reverse phase HPLC as described in step 10 of Example 3. The title compound was eluted (retention time = 24.5 and 25.6 minutes) over 30 minutes as a mixture of diastereoisomers (due to chiral P=S) with an acetonitrile gradient of 5% to 30% mixed with buffer (triethylammonium acetate, pH 5.9) . The product was further characterized by mass spectra and CE. EXAMPLE 6 Synthesis Of Chimeric Oligomers A. 5' -MMI Capped phosphorothioate: T.T.Cme*T s C s G s C s T B G s GsT s G s A s G s T s T s T s C [. = 3' -CH 2 -N(CH 3 ) -0-5' ; C e = 5-methylcytosine; s = 3' -0-P(0) (S) -0-5'] The 5'-0-trityl off phosphorothioate oligonucleotide (T s C s G s C s T s G s G s T s G s A s G s TsT s T s C) was synthesized on a DNA synthesizer in lμM scale on a CPG support utilizing standard phosphoramidite chemistry, (see, Zon in Protocols For Oligonucleotides and Analogs, pages 165-189, S. Agrawal, Humana Press, Totowa, NJ, 1993) . Next, coupling was performed with the 5' -O-phthalimido-3' -O-phosphoramidite derivative of thymidine 2$. via standard procedures to provide a protected 5'-0-amino end of the oligomer. The 5' -O-phthalimido group was deprotected generally in accordance with the procedure of step 1 of Example 3. The CPG was then washed with dichloromethane for 240 seconds. N-4-benzoyl-3' -deoxy-3' -C-formyl-5' -0- phtalimido-5-methylcytosine 7 was then coupled with the oligomer on the support following the procedure of step 3 of Example 3. The CPG was washed with dichloromethane for 150 seconds. Oxime coupling was continued one more time following steps 1-4 of Example 3 with thymidine derivative 13. Lastly, 5' -O-tert-butyl-diphenylsilyl protected thymidine 18 was incorporate utilizing steps 3-4 of Example 3. The resulting oligomer was cleaved from the support by treatment with ammonium hydroxide (2 hours, room temperature) and then heated at 55°C for 6 hours. The solution was concentrated and the residue dissolved in glacial acetic acid (2 ml) . The oxime linkages were then reduced with NaCNBH 3 (15 mg) and methylated in the manner described in step 7 of Example 3. The terminal TBDPS group was then removed by TBAF treatment as described in step 9 of Example 3. The crude, chimeric oligomer was then purified by HPLC in a manner described in step 10 of Example 3. The purified material had a retention time of 22 . 1 minutes . The chromatographic peak was broad due to a mixture of phosphorothioate diastereomers . B . 3 ' - MMI Capped Phosphorothioate : G S T S T S C S T S C B G B C S T B G S G B T B -G S A B G B T.T.T.C [s = 3 ' -0-P (=0) (s) -0- 5 ' ; * = 3 ' CH 2 N (CH 3 ) -0- 5 ' ] Synthesis of a tetrameric τ*T*T*C building block with MMI internucleosidic linkages is achieved by the procedure described in Example 23 of Application PCT/US92/04294, filed May 21, 1993, utilizing solution phase stepwise coupling. This building block is protected with a 5'-0-DMT group and is attached to CPG via standard procedures (see, Pon, R.T. in Protocols for Oligonucleotides and Analogs, pages 465-496, Agrawal, S. ed., Humana Press, Totowa, NJ, 1993) . Thus, 5' -0-DMT-T*T*T*C-CPG is packed into a 1 μM column and attached to a DNA synthesizer. The synthesis of the phosphorothioate portion is accomplished by standard phosphoramidite chemistry protocol as described in Example 6. The resulting chimeric oligomer with a 3' -MMI tail/cap is then purified by HPLC. Alternatively, the procedure described in Example 5 can be employed to prepare chimeric oligomers of any desired length and base composition. C. 3' - and 5' -MMI Capped Phosphorothioate: T.T.C*T s C B G B C B T B G B -G B T B G B A a G s T.T.T.C [. = 3' -CH 2 -N(CH 3 ) -0-5' ; s = 3'-0-P(0) (S)0-5'] Synthesis of 3' - and 5' -end capped chimeric oligomers is accomplished by combination of the methods described in Examples 3 and 5. 5'-0-DMT blocked oligomer T*τ*T*C is synthesized by incorporating appropriate building blocks (compounds ϋ, 2J3 and 13.) following the protocol described in Example 3 (steps 1-6) . The 5'-0-DMT group is removed from the CPG-attached oligomer utilizing standard acidic deprotection. Next, a phosphorothioate chain of desired length is synthesized onto the oxime tetramer. The 5'-cap of the MMI tetramer is attached following the protocol of Example 6(A) to furnish the title compound. Deprotection of oligomer from the support, reductive methylation of the oxime linkages, and purification by HPLC as in Examples 6(A) and 6(B) provides the oligomer of choice. Alternatively, appropriately protected tetramers are prepared by solution phase MMI chemistry as per Example 23 of Application PCT/US92/04294. The tetramers are then conjugated sequentially following standard phosphoramidite procedures. EXAMPLE 7 Synthesis Of Mixed Base MMI Oligomers: T.T, A * T, Cme*T, and G.T A general procedure for the synthesis of mixed base MMI linked oligomers has been developed to produce all sixteen pairs of possible dimers (X*Y; X and/or Y = T, dC, dA, dG) . The process consists of two steps on an automated DNA synthesizer ( e . g. , ABI 380 B) and two steps off the synthesizer. A. Automated Reactions 1. Deprotection of the phthalimido group of 8-12 was carried out with a 3% solution of methyl hydrazine in dichloromethane and methanol (98:2, v/v) utilizing a 630 second step, followed by a dichloromethane wash step (180 seconds) . 2. Amine-aldehyde coupling was carried out with a 0.1 M solution of a bifunctional 3'-C-formyl nucleoside ( e . g. , compounds 13.-27.) in 20 molar equivalent excess dissolved in 25% acetic acid in dichloromethane using a 630 second step, followed by a dichloromethane washing step (130 second) . The excess of bifunctional nucleosides 13 . -2J7 was recovered by simple concentration of the solutions. B. Non-automated Reactions 1. The resulting oxime oligomers (attached to CPG) were reduced and reductively methylated in manner generally in accordance with step 7 of Example 3. 2. The oligomers were cleaved from the solid support (CPG) by ammonia treatment (55°C, 5 hours) and the resulting solution was concentrated in vacuo . The residue was diluted with 300μl of water and the samples were analyzed by HPLC. A reverse phase C18 column (5 μm, 5.0 X 0.46 cm) and a short (1 cm) guard column were used with a flow-rate of 1 ml/minute. Elution with 0.05 M triethylammonium acetate (pH 7.0) mixed with acetonitrile (10%→30% for 20 minutes, 30% acetonitrile isocratic for 10 minutes) furnished clean products having the following retention times. Cme*T = 12.6 minutes A * T = 15.2 minutes T * T = 15.5 minutes G * T = 12.9 minutes T*A = 11.8 minutes G*A = 07.2 minutes Each dimer bears a 5'-0-TBDPS group, which was left on the molecule to increase lipophilicity during HPLC analysis. EXAMPLE 8 Synthesis Of 5' -O-Phthalimido-2' -deoxynucleoside Derivatives. A. 5' -O-Phthalimidothymidine, 3 . The 5' -O-phthalimidothymidine was prepared by the procedure described in the Example 6 of Application Serial No. 08/040,903. B. 2' -Deoxy-5' -O-phtalimidoadenosine, 4 . To a solution of deoxyadenosine (26.9 g, 100 mmol) in DMF (500 ml) were added N-hydroxyphthalimide (21.2 g, 130 mmol) and triphenylphosphine (34.1 g, 130 mmol) . The solution was cooled to 0°C and diisopropyl-azidocarboxylate (29.5 ml, 150 mmol) was then added dropwise. After addition, the solution was warmed to room temperature and stirred for two hours. DMF was removed under reduced pressure and the residual gum was triturated with ether (4 x 300ml) . The precipitate was recrystallized from ethanol in three crops (24.66 g, 62%. m.p. 140-142°C) . - R (DMSO-d 6 ) δ 2.28-2.40 (m, IH, H2 ) , 2.76-2.90 (m, IH, H2" ) . 4.18-4.28 (m, IH, H4') , 4.41 (d, 5.1 Hz, 2H, H5' ,H5") , 4.51-4.61 (m, IH, H3 ' ) , 5.54 (d, 4.0 Hz, IH, OH3' ) , 6.38 (t, 6.9 Hz, IH, HI') , 7.27 (s, 2H, NH2) , 7.78-7.90 (m, 4H, ar-H) , 8.12 (s, IH, H2) , 8.33 (s, IH, H8) . 13 C-NMR (DMSO-d 6 ) δ 71.00 (C4') , 77.86 (C2') , 83.66 (C3') , 84.47 (Cl') , 119.14 (C5') , 123.17 and 134.71 (C4", C5", C6", C7") , 128.48 (C3",C8") , 139.48 (C8) , 149.05 (C4) , 152.59 (C2) , 156.03 (C5, C6), 162.98 (C2",C9") . Anal. : C 18 H 16 N 6 0 5 +l/2 CH 3 OH, Calcd. : C, 53.88; H, 4.40; N, 20.38; Found: C, 53.64; H, 4.21; N, 20.22. Mass: [M+H] + 397, [A+2H] + 136. C. 2'-Deoxy-06-diphenylcarbamoyl-N2-isobutyryl-5'-O- phthalimidoguanosine, 5 . To a solution of 2'deoxy-06-diphenylcarbamoyl-N2- isobutyryl-guanosine (10.31 g, 19.36 mmoles) in THF (155 ml) and DMF (62 ml) , triphenylphosphine (7.694 g, 29.04 mmoles) and N-hydroxyphthalimide (4.88 g) were added. Diisopropyl azodicarboxylate (6.2 ml) was added to the cooled (0°C) solution over a period of 5 minutes. On complete addition, the solution was warmed to room temperature and stirred for 5 hours. The solvents were evaporated under vacuum and the residue purified by silica gel column chromatography. Elution with dichloromethane/methanol (95:5, v/v) furnished the title compound (9.04 g, 69% yield) . X H-NMR (200 MHz, DMSO- & ) δ 10.64 (l,s,2-NH), 8.59 (1, s, H-8) , 7.76 (4, s,phthaloyl) , 7.5- 7.16 (10, m, N0 2 ) , 6.40 (l,t,l'-H), 5.54 (l,d,3'-OH) , 4.64 (l,m, 3'-H), 4.48 (2, m, 5'-H, 5"-H) , 4.21 (1, m, 4'-H), 3.33 (6, d, CH (CH 3 ) 2 ) , 3.05 (l,m,2'-H), 2.68 (l,m, 2"-H) . D. N4-Benzoyl-2' -deoxy-5' -O-phthalimidocytosine, 6 TBDP-silylation of N4-benzoyl-2' -deoxy-5' -0- dimethoxytritylcytosine was carried out generally in accordance with Example 7 of Application Serial No. 08/040,903 to furnish a 3'-TBDPSi protected nucleoside. The latter compound was treated with trichloroacetic acid to deprotect the dimethoxytrityl group and furnish N4-benzoyl- 3' -O-tert-butyldiphenylsilyl-2' -deoxycytosine. 1H-NMR (200MHz, CDC1 3 ) δ 8.67 (1,broad, H) , 8.16 (1, d, H-5) , 7.9- 7.15 (16,m,TBDP, Benzoyl, 6-H) , 6.27 (l,t, l'-H) , 4.44 (l,m,3'-H), 4.035(l,m,4'-H) , 3.67 (l,dd,5'-H) , 3.245 (l,dd,5"-H) , 2.65 (l,m,2'-H), 2.25 (l,m,2"-H) , 2.06 (1,broad, 5' -OH) , 1.1 (9,s,tBu) . Mitsunobu reaction of N4-benzoyl-3' -O-tert- butyldiphenylsilyl-2' -deoxycytosine with N-hydroxyphthalimide following the procedure described above furnished 81% yield of the desired N4-benzoyl-3' -O-tert-butyldiphenylsilyl-2' - deoxy-5' -O-phthalimidocytosine. MP = 175-177°C. Η- MR (200MHz, CDC1 3 ) δ 8.61(2,d, NH,5-H) , 7.91-7.26 (20, m, benzoyl,TBDP, phthal, 6-H) , 6.545 (1, m, l'-H) , 4.70 (l,m, 3'- H) , 4.17 (l,m, 3'H) , 4.035 (l,dd, 5'-H) , 3.67 (l,dd, 5"- H),2.815 (l,m,2'-H) , 1.95 (l,m, 2"-H) , 1.18 (9,s,tBu) . Treatment of N4-benzoyl-3' -O-tert- butyldiphenylsilyl-2' -deoxy-5' -O-phthalimidocytosine with TBAF in THF furnished the title compound in 85% yield. EXAMPLE 9 Synthesis Of 2' ,3' -Dideoxy-3' -C-formyl-5' -O-phtalimido- nucleoside Derivatives. A. 3' -Deoxy-3' -C-formyl-5' -O-phtalimidothymidine, 13 5' -O-tert-Butyldiphenylsilyl-3' -C-styrylthymidine was prepared according to the procedure described in Example 82 of Application Serial No. 08/040,903 and deblocked with TBAF to provide 3' -C-styrylthymidine as a white foam in 65% yield. Anal. : C 18 H 21 N 2 0 4 Calcd.: C% 65.63; H% 6.42; N% 8.50; Found: C% 65.23; H% 6.25; N% 8.34. Mitsunobu reaction of 3' -C-styrylthymidine with N- hydroxyphthalimide gave 97% yield of 5' -O-phtalimido-3' -C- styrylthymidine as a white solid. Anal.: C 26 H 23 N 3 0 6 Calcd. : C% 65.95; H% 4.89; N% 8.87; Found: C% 65.69; H% 5.11; N% ' 8.59. Oxidative cleavage (Os0 4 /NaI0 4 ) of 5' -O-phthalimido- 3' -C-styrylthymidine was carried out as in Example 82 of Application Serial No. 08/040,903 to furnish the title compound 13. This procedure constitutes an alternate method for the preparation of bifunctional nucleosides such as compounds 13-17. B. 2' ,3' -Dideoxy-3' -C-formyl-5' -O- phthalimidoadenosine, 14 2' -Deoxyadenosine was conveniently transformed into 5' -0-tert-butyldiphenylsilyl-2' ,3' -dideoxy-3' -C- styryladenosine in 60% yield utilizing the radical reaction described in Example 82 of Application Serial No. 08/040,903. The 5'-0-TBDPS group of the latter compound was deblocked to provide 2', 3' -dideoxy-3' -C-styryladenosine in 91% yield, mp 215-217°C. Anal.: C 18 H 19 N 5 0 2 • 1/4 H 2 0 Calcd. : C% 63.23; H% 5.74; N% 20.48; Found: C% 63.31; H% 5.68; N% 20.69. 2' , 3' -Dideoxy-3' -C-styryladenosine underwent standard Mitsunobu reaction with N-hydroxyphthalimide to provide 2' ,3' -dideoxy-5' -0-phthalimido-3' -C-styryladenosine in 76% yield with a melting point of 145-147°C. Anal. : C 26 H 22 N 6 0 4 -l/4 H 2 0 Calcd. : C% 64.12; H% 4.65; N% 17.25; Found: C% 63.96; H% 4.58; N% 17.51. Oxidative cleavage (0 s 0 4 /NaI0 4 ) of the styryl group of the latter compound furnished the title compound in 55% yield as a white powder. C. N4-Benzoyl-2' ,3' -dideoxy-3' -C-formyl-5' -0- phthalimido-5-methylcytosine, 1 5' -O-tert-Butyldiphenylsilyl-3' -C-styrylthymidine was converted into its 4-triazolo derivative generally according to the procedure of Li, et al . , Biochemistry 1987, 26, 1086. The product subsequently was treated with ammonia. Benzoylation of the resulting cytosine derivative provided N4-benzoyl-5' -0-tert-butyldisphenylsilyl-2' , 3 ' -dideoxy-3' -C- styryl-5' -methylcytosine (55% yield for three steps) . Deprotection of the latter product with TBAF and Mitsunobu reaction of the product furnished N4-benzoyl-2' , 3, -dideoxy- 5' -O-phthalimido-3' -C-styryl-5-methyl-cytosine in 45% yield. Melting point = 150-155°C. Anal. : C 33 H 28 N 4 0 6 Calcd. : C% 68.74; H% 4.89; N% 9.71; Found: C% 68.33; H% 4.95; N% 9.57. This product then was treated with 0s0 4 /NaI0 4 as described in Example 82 of Application Serial No. 08/040,903 to yield title compound JL7 in 57% yield as a white powder. Anal. : C 26 H 22 N 4 0 7 -1.25 H 2 0 Calcd. : C% 59.48; H% 4.70; N% 10.67; Found: C% 59.53; H% 4.83; N% 10.58. D. 2' ,3' -Dideoxy-3' -C-formyl-N2-isobutyryl-5' -O- phthalimidoguanosine, 15 2' -Deoxyguanosine was converted into the title compound 15 . utilizing following reactions: (i) N2- isobutyrylation generally according to R.A. Jones in Oligonucleotide Synthesis, pages 24-27, M.J. Gait, ed. IRL Press, Oxford, 1984; (ii) tert-butyldiphenylsilylation generally according to Nair, Org. Prep. Proc . Int . 1990, 22, 57; (iii) phenoxythiocarbonylation generally according to Robins, J " . Am. Chem. Soc. 1983, 105, 4059; (iv) styrylation generally according to Example 82 of Application Serial No. 08/040,903; (v) desilylation by treatment with 1 M TBAF in THF; (vi) Mitsunobu reaction generally according to Example 6 of Application Serial No. 08/040,903; and (vii) oxidative cleavage generally according to Example 82 of Application Serial No. 08/040,903. ~ ~E NMR (CDC1 3 ) δ 1.23 (m, 6, ibu H) , 2.50 (m, 1, 2' H) , 2.60 (m, 1, 2"H), 2.87 (m, 1, CH-ibu) , 3.81 (m, 1, 5"CH2), 4.1-4.4 (m, 3, 3'H, 4'H, 5"CH2), 6.03 (m, 1, l'H) , 7.5-8.2 (m, 4, ArH) , 8.08 (s, 1, C8H) , 9.79 (s, 1, CHO) , 12. 24 (s, 1, NH) . EXAMPLE 10 Synthesis Of 2' ,3' -Dideoxy-5' -O-FMOC-3' -C-formylnucleosides. A. 3' -Deoxy-5' -O-FMOC-3' -C-formylthymidine, 23 3' -Deoxy-3 ' -C-styrylthymidine was protected with FMOC-C1 generally according to Balgobin, et al . , Nucleosides and Nucleotides 1987, 6, 461, to furnish 5' -O-FMOC-3' -deoxy- 3' -C-styrylthymidine in 96% yield as a yellow foam. Anal. : C 33 H 30 N 2 O 6 -l/2 H 2 0 Calcd. : C% 70.82; H% 5.58; N% 5.00; Found: C% 70.53; H% 5.48; N% 4.98. Oxidative cleavage (O s 0 4 /NaI0 4 ) of the former compound gave title compound 2_3 in 57% yield. X H NMR (CDC1 3 ) δ 1.80 (s, 3, CH 3 ) , 2.22, 2.71 (2m, 2, 2'CH 2 ) , 3.15 (m,l,3' CH) , 4.22 (t, 1, CH FMOC) , 4.45 (s, 2, CH 2 FMOC) , 4.55 (m, 2, 5' CH 2) , 4.62 (m, 1, 4'H) , 6.06 (t, 1, l'H) , 7.3-7.80 (m, 9, Ar H, C6H) , 8.3 (br s, 1, NH) , 9.75 (s, 1, CHO) . In an analogous manner, 3 '-C-styryl nucleoside derivatives of 2' -deoxycytidine, 2' -deoxyadenosine, and 2'- deoxyguanosine are transformed into 3' -C-formyl-5' -O-FMOC- derivatives of 2' -deoxycytidine 2JL, 2' -deoxyadenosine 2_4, and 2' -deoxyguanosine .25 . , respectively. EXAMPLE 11 Deprotection Assay During Automated Synthesis Utilizing Emission Spectra Equipment and Materials: Luminescence Spectrophotometer: PERKIN ELMER LS50B Solvent: Spectrophotometer grade MeOH Reagents: (i) 1,2-dihydro-4-hydroxy-2-methyl-l- oxσphthalazine (MW 176.175) ; (ii) N-methyl hydrazine (MW 46.07, d 0.866) ; (iii) N-hydroxyphthalimide (MW 163.13) Synthesis: 1,2-Dihydro-4-hydroxy-2-methyl-l- oxophthalazine N-Hydroxyphthalimide (10 g, 59.5 mmoles) was dissolved in anhydrous CH 2 C1 2 (300 ml) and N-methyl hydrazine (9.7 ml) was added to the stirred solution. The solution turned red and then yellow. When all the starting material had disappeared, the solvent was evaporated and the resulting oil was crystallized from anhydrous ethanol as fine needles. Analysis Protocol A. Neutral conditions The spectrometer was turned on 0.5 hour prior to the measurement . A blank run was performed using spectrophotometer grade methanol. 1,2-Dihydro-4-hydroxy-2- methyl-1-oxophthalazine (0.234 mg) was then dissolved in methanol (100 ml) and the sample analyzed on the spectrophotometer. The excitation wavelength was chosen at 298 nm. and the corresponding emission was observed at 400 nm. The following concentrations (μMol) of 1,2-Dihydro-4- hydroxy-2-methyl-1-oxophthalazine were tested: A linear plot was obtained using the equation : Emission = [21 . 0 x 10 s ] • [Concentration (mol/L) ] B. Basic conditions The procedure of Example 11 (A) was repeated except that the oxophthalazine sample was basified by addition of N- methyl hydrazine (1% volume) . Basification results in the decay of emission intensity by 25 units and moves the excitation wavelength to 485 nm. C. Acidic conditions. The procedure of Example 11 (A) was repeated except that the oxophthalazine sample was acidified with glacial acetic acid (0.1 ml) . The intensities of the emission was enhanced considerably and the values are summarized below. A graphical representation of this data provided a linear plot using the following equation: Intensity = [459 x 10 6 ] • [Concentration (mol/L) ] As can be seen, sensitivity of detection was enhanced dramatically under acidic conditions. The foregoing method is very effective for the determination of low concentrations of 1, 2-Dihydro-4-hydroxy-2-methyl-1- oxophthalazine during automated synthesis . EXAMPLE 12 Solution Phase/Block Synthesis Of Chimeric Oligomers I. General Procedures: A. Coupling Of An O-Amino Nucleoside To An Aldehydo Nucleoside. An equimolar mixture of 5' -O-amino nucleoside and 3'- deoxy-3' -C-formyl nucleoside were dissolved in 1:1 toluene/CH 2 Cl 2 containing several drops of acetic acid, mixed at 35 °C on a rotary evaporator at atmospheric pressure for 1 hour, then concentrated to a foam under reduced pressure. This process was repeated until TLC analysis (5% MeOH/CH 2 Cl 2 ) showed the reaction to be complete (3-6 times) , with the intermediate oxime evident as the only major spot. For MMI dimers in which one of the starting nucleosides bears an amide protecting group on the base (for example i^-benzoyl-S- methylcytosine) , the oxime was stirred overnight with methanolic ammonia, and the resulting solution concentrated to provide the crude product. The so obtained intermediate, base unprotected oxime dimer was dissolved in glacial acetic acid (0.1 M) , placed in an ice bath, and sodium cyanoborohydride (3 x 2 eq) was added over 15 minutes. The mixture was allowed to warm to room temperature over 1 hour, placed in an ice bath, and aqueous formaldehyde (20 eq, 20%) was added in one portion. Sodium cyanoborohydride (3 x 2 eq) was added over 30 minutes, and the mixture was allowed to warm to room temperature over 1 hour. The reaction was terminated by pouring into ice water (5 times volume) with vigorous stirring. The resulting residue was extracted into CH 2 C1 2 , concentrated, azeotroped (3 times) with toluene, and chromatographed. The column was eluted with 1 to 5% EtOH (95%) /EtOAc, which removed several trace impurities off the column, and the desired product was then obtained by elution with 10% MeOH/CH 2 Cl 2 , and concentration of the appropriate fractions. B. A^-Benzoylation of Cytosine-containing MMI Dimers. The dimer (1 eq) was dissolved in dry DMF, benzoic anhydride (1.1 eq) was added in one portion, and the reaction stirred at room temperature overnight. The solvent was removed, the residue partitioned between 5% aqueous sodium bicarbonate and CH 2 C1 2 , the organic layer was washed with water, dried over magnesium sulfate, concentrated in vacuo, and chromatographed to afford pure product. C. Desilylation of MMI Dimers. The silylated MMI dimer was dissolved in dry THF (0.1 M) and cooled in an ice bath. A solution of tetrabutylammonium fluoride in THF (1 M, 1.5 eq per silyl group) was added dropwise over 5 minutes. The solution was stirred at 0 °C until the reaction was complete as judged by TLC (1-2 hours) , at which point silica (5 g/mmol) was added, and the mixture carefully concentrated. The silica was applied to a column packed in 5% MeOH/CH 2 Cl 2 , and eluted with 5% to 10% MeOH/CH 2 Cl 2. The appropriate fractions were combined, concentrated, and the residue azeotroped with EtOAc to provide the silylated product . D. Dimethoxytritylation of MMI Dimers. The appropriate dimer (1 eq) and N, N-dimethyl- aminopyridine (0.1 eq) was azeotroped 3 times with dry pyridine, then dissolved in the minimum amount of dry pyridine. Triethylamine (2 eq) and 4,4' -dimethoxytrityl chloride were added to the stirred solution at room temperature, and the mixture diluted with CH 2 C1 2 (ca 5 mL/mL pyridine) . Stirring was continued until the reaction was complete (typically overnight) as judged by TLC (10% MeOH/CH 2 Cl 2 + 0.1% Et 3 N) , methanol was added to quench the reaction, and the reaction mixture extracted with 5% aqueous sodium bicarbonate. The organic layer was dried (trace magnesium sulfate) , filtered, and concentrated to afford a syrup, which was chromatographed on silica gel (CH 2 C1 2 + 0.1% Et 3 N to 10% MeOH/CH 2 Cl 2 + . 0.1% Et 3 N) . Fractions containing only product were combined and concentrated, and azeotroped with EtOAc to afford the 5' -dimethoxytritylated intermediate as a hard foam. This material was judged to be pure by X H NMR, and used without further purification. E. Phosphitylation of MMI Dimer. The appropriate 5' -O-dimethoxytrityl derivative was azeotroped with dry acetonitrile 3 times, then dissolved in dry dichloromethane (0.1 M) at room temperature. Diisopropylammonium tetrazolide (0.5 eq) and 2-cyanoethyl- N,_Z\T,_N ' / _N ' -tetraisopropylphosphorodiamidite (1.2 eq) was added, and the reaction allowed to stir at room temperature until complete (typically overnight) as judged by TLC (EtOAc + 0.1% Et 3 N) . The reaction mixture was then directly loaded onto a column packed with 25% EtOAc/hexane + 0.1% Et 3 N, and eluted with a stepwise gradient to EtOAc + 0.1% Et 3 N. Fractions containing only the product were pooled and concentrated to yield a hard foam, which was lyophilized from dry 1,4-dioxane to afford the phosphoramidite as a fine white powder. II. Synthesis of 5' -0-DMT-TT BlMβ C Bz T-0-phosphoramidite-3' MMI tetramer. 5' -O-TBDPS-3' -C-formyl-T*T oxime dimer. 5' -O-TBDPS-3' -deoxy-3' -C-formyl-thymidine (prepared according to Sanghvi et al . Synthesis 1994, 1163) (0.229 mmole, leq.) and 5' -O-amino-3' -deoxy-3 ' -C-styryl-thymidine (prepared according to the procedure in Example 9 above) (0.229 mmole, leq.) were coupled according to the general procedure described above. The crude oxime dimer was then evaporated and dissolved in (1/1 : v/v) mixture of water and 1,4-dioxane with NaI0 4 (0.503 mmole, 2.2 eq, ) osmium tetroxide (4% solution in water, 0.229 mmole, O.leq.), 4-methyl-morpholine-N-oxide (0.332 mmole, 1.45 eq.) before being stirred in the dark for 4 hours. After work-up (same as described in the example 9 above) , the residue was chromatographed on silica gel column with 5% MeOH/CH 2 Cl 2 to yield 36% (0.082 mmole) of a white foam. R f = 0.33 (10% MeOH/CH 2 Cl 2 , MS (Electrospray) , M + H = 744.5, -NMR (DMSO-d 6 ) δ 11.30 (ss, 2, NH) , 9.64 (br s, 1, CHO) , 6.10 (m, 2, l'H) , 3.60- 4.52 (m, 8, H3', H4' , H5' , H5' ' ) , 1.76 (s, 3, CH 3 , thymine) , 1.55 (s, 3, CH 3 , thymine) . 5'-0-Amino-3'-0-TBDPS- Mβ C Bz *T oxime dimer. 5' -O-phthalimido-3' -deoxy-3' -C-formyl-5-methyl-i^-benzoyl- cytidine (0.150 mmole, leq.) and 5' -O-amino-3' -O-TBDPS- thymidine (0.15 mmole, leq.) in CH 2 C1 2 were coupled following the general procedure described above. The crude oxime dimer was then concentrated under vacuo, neutralized with a 5% aqueous solution of sodium bicarbonate (50 ml) extracted with CH 2 C1 2 , washed with water and brine (50 ml each) dried over sodium sulfate and finally evaporated to dryness. TLC of the reaction mixture revealed the presence of a single product (R f = 0.65 10% MeOH/CH 2 Cl 2 ) . Without further purification, this compound was dissolved in CH 2 C1 2 (5 ml) and N-methyl hydrazine (0.225 mmole, 1.5 eq.) was added at room temperature. After 4 hours stirring, the white precipitate was filtered off and the filtrate concentrated and chromatographed on silica gel column. Elution with a mixture of 0.5% to 5% MeOH/CH 2 Cl 2 to yield 51 of a white solid. R f = 0.55 (10% MeOH/CH 2 Cl 2 ) , MS (Electr spray), M + H = 850, , M + Na = 872, 'H-NMR (DMSO-d 6 ) , 11.34 (s, 2, NH) , 6.30 (pt, 3, NH 2 + l'H) , 6.05 (pt, 1, l'H, thymidine) , 3.57-4.45 (m, 8, H3' , H4' , H5', H5' ' ) , 2.06 (s, 3, CH 3 , C-5 CH 3 ) , 1.74 (s, 3, CH 3 , thymine) . 5'-0-TBDPS-3'-0-TBDPS-T*T* Mβ C Bl *T MMI tetramer. An equimolar mixture of 5' -O-TBDPS-3' -C-formyl-T*T oxime dimer and 5' -O-amino-3' -0-TBDPS- Me C Bz *T oxime dimer (0.153 mmole, 1 eq.) were coupled following the general procedure described above. The MMI tetramer was purified by silica gel column chromatography using 3% MeOH/CH 2 Cl 2 to yield 48% over four synthetic steps (oxime coupling, debenzoylation, reductive methylation and rebenzoylation) of the desired compound. R f = 0.40 (10% MeOH/CH 2 Cl 2 ) , MS (Electrospray) , M + H = 1622.9, , M + Na = 1644.3, 'H-NMR (DMSO-d 6 ) δ 11.32 (m, 4, NH) , 6.27 (pt, 1, l'H, 5 methyl cytidine) , 6.05 (m, 3, l'H, thymidine), 2.02 (s, 3, CH 3 , 5 methyl cytidine), 1.73 (d, 6, CH 3 , thymine) , 1.51, (s, 3H, CH 3 , thymine) . 5'-HO-T*T* Mβ C Bz *T-OH-3' MMI tetramer. 5' -0-TBDPS-T*T* Me C Bz *T-0-TBDPS-3' MMI tetramer (0.070 mmole, 1 eq.) was desilylated according the general procedure described above. Deblocked MMI tetramer was purified by silica gel column chromatography. Elution with 5% MeOH/CH 2 Cl 2 , pooling and evaporation furnished 80% of the title compound. R f = 0.56 (15% MeOH/CH 2 Cl 2 ) , MS (Electrospray) , M + H = 1146.2, M + Na = 1168. 5'-0-DMTr-T*T* Mβ C Bz *T-OH-3' MMI tetramer. 5'-HO-T*T* e C Bz *T-OH-3' MMI tetramer (0.070 mmole, leq.) was dimethoxytritylated according the general procedure described above. Protected MMI tetramer was purified by silica gel column chromatography. Elution with 5% MeOH/CH 2 Cl 2 , pooling and evaporation furnished 81% of the title compound. R f = 0.47 (12% MeOH/CH 2 Cl 2 ) , MS (Electrospray) , M + H = 1448, M + Na = 1469.7. 5'-0-DMTr-T*T* Mβ C Bz *T-0-phosphoramidite-3' MMI tetramer. 5'-0-DMTr-T*T* Me C Bz *T-OH-3' MMI tetramer (0.045 mmole, 1 eq.) was phosphitylated according the general procedure described above. MMI tetramer was eluted from the silica gel column chromatography with 5% MeOH/CH 2 Cl 2 to yield 85% of the desired compound. R f = 0.53 (10% MeOH/CH 2 Cl 2 ) , 31 P NMR (CD 3 CN) δ 148.55, 148.44. Ill : Synthesis Of 5'-0-DMT- T*T*T*C Bz -OH-3' MMI tetramer. 5' -0-amino-T*BzC-0-TBDPS-3' oxime dimer. 5' -O-Phtalimido-3' -deoxy-3' -C-formyl-thymidine (0.450 mmole, 1 eq.) and 5' -O-amino-3' -O-TBDPS-i^-benzoyl-cytidine (0.45 mmole, 1 eq.) in CH 2 C1 2 were coupled following the general procedure described above. The crude product was then concentrated under vacuo, neutralized with a 5% aqueous solution of sodium bicarbonate (50 ml) extracted with CH 2 C1 2 , washed with water and brine (50 ml each) dried over sodium sulfate and finally evaporated to dryness. TLC revealed the presence of a single product (R f = 0.65 10% MeOH /CH 2 Cl 2 ) . Without further purification, this compound was dissolved in CH 2 C1 2 (15 mL) and N-methylhydrazine (0.675 mmole, 1.5 eq.) was added at room temperature. After 4 hours of stirring, the white precipitate was filtered off and the filtrate concentrated and chromatographed on silica gel column with a mixture from 0.5% to 5% MeOH/CH 2 Cl 2 to yield 65% of a white solid. R f = 0.48 (10% MeOH/ CH 2 C1 2 ) , MS (Electrospray) , M + H = 836, M + Na = 858, 'H-NMR (DMSO-d 6 ) δ 11.28 (br s, 2, NH) , 6.22 (pt, 1, NH 2 + l'H, 5- methylcytidine) , 6.05 (pt, 1, l'H, thymidine) , 3.57-4.45 (m, 8H, H3', H4', H5', H5" ) , 1.81 (s, 3, CH S , thymine) . 5'-0-TBDPS-T*T*T*C Bz -0-TBDPS-3' MMI tetramer. An equimolar mixture of 5' -O-TBDPS-3' -C-formyl-T*T oxime dimer and 5' -0-amino-T*BzC-0-TBDPS-3' oxime dimer (0.343 mmole, 1 eq.) in CH 2 C1 2 were coupled following the general procedure described above. The MMI tetramer was purified by silica gel column chromatography using 3% MeOH/CH 2 Cl 2 to yield 56% over four synthetic steps (oxime coupling, debenzoylation, reductive methylation and rebenzoylation) of the title compound. R f = 0.35 (10% MeOH/CH 2 Cl 2 ) , MS (Electrospray), M + H = 1607.9, , M + Na = 1630.2, 'H-NMR (DMSO-d 6 ) δ 8.6, 8.9, 9.3 (m, 4, NH) , 6.35 (pt, 1, HI', cytidine) , 6.05 (m, 3, HI', thymidine) , 5.95 (m, 2H, HI', thymidine), 1.88 (d, 6H, CH 3 , thymidine) , 1.61 (s, 3H, CH 3 , thymine) . 5'-OH-T*T*T*C Bz -OH-3' MMI tetramer. 5'-0-TBDPS-T*T*T*C Bz -0-TBDPS-3' MMI tetramer (0.143 mmole, 1 eq.) was desilylated following the general procedure described above. MMI tetramer was purified by silica gel column chromatography using 5% MeOH/CH 2 Cl 2 to yield 80% of the title compound. R f = 0.34 (15% MeOH/CH 2 Cl 2 ) , MS (Electrospray) , M + H = 1131.0; M + NH 4 = 1167.3. 5'-0-DMTr-T*T*T*C Bz -OH-3' . 5' -OH-T*T*T*C Bz -OH-3' MMI tetramer (0.113 mmole, leq.) was dimethoxytritylated following the general procedure described above. MMI tetramer was purified by silica gel column chromatography. Elution with 5% MeOH/CH 2 Cl 2 , pooling and evaporation furnished 81% yield of the desired compound. R f = 0.33 (12% MeOH/CH 2 Cl 2 ) ; MS (Electrospray) M + H = 1435.6; M + Na = 1456.8; 'H NMR (DMS0-d 6 ) δ 9.5 (m, 4, NH) , 6.15 (pt, 1, HI', cytidine) , 6.01 (m, 3, HI', thymidine) . IV. Synthesis of Oligomers Incorporating MMI Tetramers. Tetameric MMI containing oligonucleotides correspond to chimeric oligonucleotides where several phosphodiesters and/or phosphorothioates linkages have been replaced by at least three consecutive methylene (methyl) imino (MMI) internucleosidic link. MMI tetramer (or longer chain) containing chimeric oligonucleotides can be - synthesized using standard phosphoramidite chemistry. In this case the chimeric oligomers were synthesized attached to CPG (Controlled Pore Glass) solid support and the assembling was performed on an automated DNA synthesizer such as Millipore Expedite or Applied Biosystem 380B. The MMI tetramers synthesized as phosphoramidite elongation units (DMT-X*X*X*X-phosphoramidite, X = T, C, 5Me C, * = 3' -CH 2 -N(CH 3 ) -0-5' or X*X*X*X MMI ) were prepared according the procedure described above. The initial deoxynucleoside or MMI tetramer determining the 3'-end of the MMI containing chimeric oligonucleotide was loaded on to the CPG solid support via a succinyl linkage following the procedure described in Example 2 above (for example: 5' -0-DMTr-T*T*T*C-0- (succinyl-CPG-NMe 2 ) -3' MMI was loaded onto the CPG providing a loading of 22.67 mmole/g) . The chain elongation of chimeric oligomers was performed in a similar manner as described for the MMI phosphoramidite Dimers. Table 1 : Chimeric Oligomers Containing T*T*T*C and τ*T* Mβ C*T MMI Tetramers. Analytical Data Column Supelco LC 18 15cm x 4.6mm, 5mm, 5% to 25% CH 3 CN in 0.05M TEAA, pH 7.00 over 25 minutes, 1ml/min. EXAMPLE 13 Synthesis of New Monomeric Nucleosides 5' -O-Phthalimido-2' -fluorothymidine. 2' -Fluorothymidine was prepared according to the known procedure (Kawasaki et al . J. Med. Chem. 1993, 36, 83-1) . To this material (1.95 g, 7.5 mmol) and N-hydroxyphthalimide (1.29 g, 7.88 mmol) in dry DMF (60 mL) was added diethyl azodicarboxylate (1.24 mL, 7.88 mol) dropwise at room temperature of 0.5 hour. The mixture was stirred overnight and poured into a rapidly stirred ice cold mixture of ether (150 mL) and water (150 mL) . The aqueous layer was slowly diluted to a total volume of 350 mL with cold water, at whic point solid began forming. The ether was decanted, an additional portion ether was added, stirred, and decanted, and the process repeated. The solution was now diluted to a total volume of 500 mL with water, and allowed to stand on ice for several hours. The solid was collected, and dried t afford 2.11 g (70%) of a white powder: R f 0.31 (5% MeOH/CH 2 Cl 2 ) ; Η NMR (CDC1 3 ) δ 8.84 (s, IH, NH) , 7.90-7.70 (m, 4H) , 7.26 (s, IH, H-6) , 6.03 (dd, J=3.0, 17.0 Hz, IH, H-l') , 5.11 (ddd, J=1.5, 3.0, 52.8 Hz, IH, H-2') , 4.75 (m, IH) , 4.56 (m, 2H) 4.34 (m, IH) , 3.26 (br s, IH) , 1.94 (s, 3H, CH 3 ) . Anal. Calcd for C 18 H 16 N 3 0 7 F«l/4Et 2 0: C, 53.84; H, 4.40; N, 9.91. Found: C, 53.52; H, 4.60; N, 9.96. 5' -O-Amino-2' -fluorothymidine. 5' -O- hthalimido-2' -fluorothymidine (1.2 g, 3 mmol) was dissolved in 30 mL of 10% MeOH/CH 2 Cl 2 with slight warming, then cooled on ice. When the reaction mixture became cloudy, methylhydrazine (0.24 mL, 4.5 mmol) was added dropwise. The clear reaction mixture was stirred for 1.5 hours at 0 °C, then applied directly onto a column packed with 10% MeOH/CH 2 Cl 2 . Elution with the same solvent, concentration of the appropriate fractions, and recrystallization of the residue from EtOH provided 0.54 g (65%) of needles: mp 168- 169 °C; R f 0.32 (10% MeOH/CH 2 Cl 2 ) ; Η NMR (DMSO-d e ) δ 11.43 (s, IH, NH) , 7.55 (s, IH, H-6) , 6.23 (s, 2H, ONH 2 ) , 5.89 (dd, J=2.0, 19.5 Hz, IH, H-l') , 5.69 (d, IH, 3'-OH) , 5.09 (ddd, J=2.0, 2.5, 53.3 Hz, IH, H-2') , 4.25-3.65 (m, 4H) , 1.80 (s, 3H, CH 3 ) . Anal. Calcd for C 10 H 14 N 3 O 5 F: C, 43.64; H, 5.13; N, 15.27. Found: C, 44.00; H, 5.01; N, 15.06. 5' -O-P thalimidouridine. To a stirred solution of uridine (4.88 g, 20 mmol) , triphenylphosphine (5.76 g, 22 mmol) , and N- hydroxyphthalimide (3.58 g, 22 mmol) was added dropwise diethyl azodicarbohydrate (4.35 g, 25 mmol) over a period of 3 hours at room temperature. The reaction mixture was stirred at room temperature for 12 hours . The solvent was removed under reduced pressure and the residue suspended in CH 2 C1 2 (300 mL) . The suspension was poured onto ice water (250 mL) and stirred vigorously to provide pale yellow precipitation. The solids were filtered and washed with water (3 x 50 mL) and ether (3 x 50 mL) . The powder was dried under vacuum to provide 3.03 g (39%) of the title compound. 'H NMR (DMSO-d 6> δ 4.05-4.17 (m, 3, 2', 3', 4' H) , 4.38 (m, 2, 5' CH 2 ) , 5.36 and 5.55 (2d, 2, 2', 3' OH) , 5.62 (d, 1, C5H) , 5.78 (d, 1, l'H), 7.77 (d, 1, C6H) , 7.90 (m, ArH), 11.37 (br s, 1, NH) . 5' -O-Phthalimido-5-methyluridine. To a stirred mixture of 5-methyluridine (51.64 g, 0.2 mol) , triphenylphosphine (57.64 g, 0.22 mol) and N- hydroxyphthalimide (35.86 g, 0.22 mol) was added dropwise diethyl azodicarboxylate (43.5 g, 0.25 mol) over a period of 4 hours at =5 °C. After complete addition, reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction was =50% (TLC, CH 2 Cl 2 :MeOH, 9:1, v/v) complete at this point of time. Therefore, additional quantities of triphenylphosphine (28.8 g, 0.11 mol), N-hydroxyphthalimide (17.9 g, 0.11 mol) and diethyl azodicarboxylate (21.7 g, 0.12 mol) were added in the manner described above. After second addition, the reaction mixture was stirred at room temperature for 16 hours. The reaction was =90% (TLC) complete at this time, therefore, solution was concentrated under vacuum to provide a thick syrupy residue. The residue was poured into a vigorously stirred mixture of ether:ice water (500 mL:1000 ml) to precipitate the product. The precipitate was filtered, washed with water (3 x 100 mL) and ether (3 x 50 ml) , and dried over P 2 0 5 to provide 56 g (69%) of the title compound. An analytical sample was crystallized from EtOH:CH 2 Cl 2 , mp 236-237 °C; Η NMR (DMSO-d 6 ) δ 1.78 (s, 3, CH 3 ) , 4.12 (m, 2', 3', 4' H) , 4.36 (m, 2, 5'CH 2 ) , 5.45 and 5.62 (2d, 2, 3', 4' OH), 7.78 (s, 1, C6H) , 7.90 (m, 4, ArH) , 11.32 (brs, 1, NH) ; Anal. Calcd for C 18 H 17 N 3 0 8 • 1/4 H 2 0: C, 53.00; H, 4.32; N, 10.30; Found: C, 53.04; H, 4.28; N, 10.19. 2' -O-Methyl-5' -O-phthalimidouridine. A stirred mixture of 5' -O-phthalimidouridine (1.94 g, 5 mmol) , dibutyltin oxide (1.48 g, 6 mmol) , tetrabutylammonium iodide (2.02 g, 5.5 mmol) and methyliodine (2.82 g, 20 mmol) in DMF (10 ml) was heated in a sealed flack at 50 °C for 16 hours under argon atmosphere. The reaction mixture was cooled (=10 °C) and to this another addition of methyl iodide (2.82 g, 20 mmol) was made. The flask was sealed and heating continued for 16 hours. The reaction mixture was cooled to room temperature and diluted with CH 2 C1 2 (50 ml) . The CH 2 C1 2 suspension was transferred onto the top of a prepacked silica gel (CH 2 C1 2 ) column. Elution with CH 2 C1 2 /CH 2 C1 2 :MeOH (9:1, v/v) furnished the desired product as homogenous material . Appropriate fractions were pooled and concentrated to provide 0.6 g (29%) of the title compound (contaminated with 20% of the 3'-0-methyl isomer) and 0.61 g (31%) of the unreacted starting material. An analytically pure sample was obtained by fractional crystallization from EtOH:Et 2 0; mp 225-228 °C; Η NMR (DMSO-d 6 ) δ 3.35 (s, 3, OCH 3 ) , 3.83, 4.15, and 4.22 (3 m, 3, 2', 3', 4' H) , 4.40 (m, 2, 5' CH 2 ) , 5.42 (d, 1, 3' OH) , 5.61 (d, 1, C5H) , 5.84 (d, 1, 1' H) , 7.78 (d, 1, C6H) , 7.84 (m, 4, ArH) and 11.4 (br s, 1, NH) ; Anal. Calcd for C 18 H 17 N 3 0 8 : C, 53.60; H, 4.24; N, 10.41; Found: C, 53.25; H, 4.34; N, 10.20. 2' -O-Methyl-5' -O-phthalimido-5-methyluridine. The title compound was synthesized in 61% yield (contaminated with =10% of 3'-0-methyl derivative) starting from 5' -O-phthalimido-5-methyluridine following the foregoing procedure. An analytical sample was obtained by crystallization (EtOH/CH 2 Cl 2 ) mp 213-214 °C; Η NMR (DMSO-d 6 ) δ 1.71 (s, 3, CH 3 ) , 3.58 (s, 3, OCH 3 ) , 4.42 (m, 2, 5' CH 2 ) , 4.63 (m, 1, 4'H) , 5.36 (m, 1, 2' H) , 5.61 (m, 1, 3' H) , 5.90 (s, 1, 1' H) , 7.50 (s, 1, C6H) , 7.82 (m, 4, ArH) , 11.55 (br s, t, NH) . 3' -O-tert-Butyldiphenylsilyl-2' -O-methyl-5' -O- phthalimido-5-methyluridine. [Note: The silylation procedure allowed a clean separation of desired 2'-0-methyl derivative from the undesired 3'-0-methyl derivative via silica gel chromatography] A mixture of 2' -O-methyl-5' -O-phthalimido-5- methyluridine (12.0 g, 28.7 mmol) , imidazole (5.86 g, 86.3 mmol) and tert-butyldiphenylsilylchloride (16.0 g, 57.5 mmol) in DMF (100 mL) was stirred at room temperature for 16 hours under an argon atmosphere. The reaction mixture was concentrated under vacuum to 1/4 of its volume and poured into ice water (500 mL) . The aqueous mixture was extracted with CH 2 C1 2 (2 x 250 mL) and washed with water (2 x 100 mL) and dried (MgS0 4 ) . The CH 2 C1 2 extract was concentrated and the residue was purified by silica gel chromatography. Elution with ether: hexanes (9:1, v/v) furnished the desired product as homogenous material . Appropriate fractions were pooled and concentrated to provide 10.51 g (55.8%) of the title compound. Η NMR (CDC1 3 ) δ 1.14 (s, 9, SiMe 3 ) , 1.90 (s, 3, CH 3 ) , 3.26 (s, 3, OCH 3 ) , 3.38 (m, 1, 4Η) , 4.08 (m, 1, 2' H) , 4.23 (m, 2, 5' CH 2 ) , 4.50 (m, 1, 3' H) , 6.08 (d, 1, 1' H) , 7.34-7.42 (m, 10, Ar H) , 7.60 (s, 1, C6 H) , 7.65-7.85 (m, 4, Ar H) , 8.08 (br s, 1, NH) ; Anal. Calcd for C 35 H37N 3 0 8 Si : C, 64.10; H, 5.68; N, 6.40; Found: C, 63.96; H, 5.67; N, 6.16. 5' -O-Amino-3' -O-tert-butyldiphenylsilyl-2' -O-methyl-5- methyluridine. To a stirred solution of 3' -O- ert-butyldiphenylsilyl- 2' -O-methyl-5' -O-phthalimido-5-methyluridine (3.1 g, 4.9 mmol) in CH 2 C1 2 (75 mL) was added methylhydrazine (0.39 mL, 7.5 mmol) in one portion at 0 °C. The reaction mixture was allowed to come to room temperature and stirred for 2 hours. The precipitate was filtered and washed with cold (=10 °C) CH 2 C1 2 (2 x 25 ml) . The combined filtrates were concentrated and the residue was purified by silica gel column chromatography. Elution with CH 2 Cl 2 :MeOH (9:1, v/v) furnished the desired product as homogenous material. Appropriate fractions were pooled and evaporated to yield 7.04 g of the title compound as a white foam. 'H NMR (CDC1 3 ) δ 1.11 (s, 9, SiMe 3 ) , 1-82 (s, 3, CH 3 ) , 3.24 (m, 1, 2' H) , 3.38 (s, 3, OCH 3 ) , 3.63 and 3.96 (dd, 2, 5' CH 2 ) , 4.11 and 4.19 (2m, 2, 3', 4' H) , 5.32 (br s, 2, 0NH 2 ) , 5.93 (d, 1, 1' H) , 7.30 (s, 1, C6H) , 7.37-7.50 and 7.63-7.73 (m, 10, Ar H) and 9.22 (br s, 1, NH) ; Anal. Calcd for C 27 H 35 N30 6 Si • 1/4 H 2 0: C, 61.16; H, 6.74; H, 7.92; Found: C, 61.03; H, 6.56; N, 7.86. J^-benzoyl-S' -0-terfc-butyldiphenylsilyl-5-methyl-2' - deoxycytidine. To i^-benzoyl-δ' - O- ert-butyldimethylsilyl-3 ' - O- tert- butyldiphenylsilyl-5-methyl-2' -deoxycytidine (7.55 g, 10.8 mmol) in dry CH 2 C1 2 (110 mL) at 0 °C was added TMS0T f (6.3 mL, 32.4 mmol) dropwise over 5 minutes. The reaction was stirred 1 hour at 0 °C, and 100 mL ice cold saturated aqueous NaHC0 3 was added, and the mixture allowed to come to room temperature with vigorous stirring over 1 hour. The organic layer was separated, washed with water, dried over magnesium sulfate, concentrated, dissolved in the minimum amount of CH 2 C1 2 and loaded onto a column packed in hexanes . Elution with 0 to 50% EtOAc/hexane provided 2.13 g (28%) of unreacted starting material, and 4.24 g (67%) of the desired product as a foam: R f 0.42 (30% EtOAc/hexane); Η NMR (CDC1 3 ) δ 8.30 (d, 2H) , 7.69-7.36 ( , 14H) , 6.26 (t, J=6.8 Hz, IH, H-l') , 4.46 (m, IH) , 4.00 (m, IH) , 3.68 (m, IH) , 3.27 (m, IH) , 2.45- 1.92 (m, 2H) , 2.04 (s, 3H, CH 3 ) , 1.09 (s, 9H) . Anal. Calcd for C 33 H 37 N 3 0 5 Si: C, 67.90; H, 6.39; N, 7.20. Found: C, 67.60; H, 6.34; N, 7.15. 5' -O-Phthalimido-i^-benzoyl-3' -O-tert- butyldiphenylsilyl-5-methyl-2' -deoxycytidine. To a suspension of i^-benzoyl-S' -O- ert- butyldiphenylsilyl-5-methyl-2' -deoxycytidine (8.1 g, 14 mmol) and N-hydroxyphthalimide (2.6 g, 16 mmol) in dry THF (300 mL) was added diethyl azodicarboxylate (1.24 mL, 7.88 mol) dropwise at room temperature of 0.5 hour. The mixture was stirred overnight, concentrated, and the residue chromatographed (2% Me0H/CH 2 Cl 2 ) to afford 10.5 g (103%) of slightly impure product, which was suitable for use in further reactions. A sample was recrystallized from ether/hexane (83% recovery) for analysis: J? f 0.47 (30% EtOAc/hexane) ; Η NMR (CDC1 3 ) δ 13.32 (s, IH) , 8.33 (d, 2H) , 7.90-7.35 (m, 18H) , 6.56 (dd, J=3.4, 5.4 Hz, IH, H-l') , 4.80 (m, IH) , 4.15-3.55 (m, 3H) , 2.60-1.95 (m, 2H) , 2.16 (s, 3H, CH 3 ) , 1.13 (s, 9H) . Anal. Calcd for C 41 H 40 N 4 O 7 Si»H 2 O: C, 65.93; H, 5.67; N, 7.50. Found: C, 65.59; H, 5.56; N, 7.39. 5' -O-Amino-i^-benzoyl-S' -O-terfc-butyldiphenylsilyl-5- methyl-2' -deoxycytidine. To 5' -0-phthalimido-.rø 4 -benzoyl-3' - O- tert- butyldiphenylsilyl-5-methyl-2' -deoxycytidine (10.2 g, 14 mmol) in 140 mL of CH 2 C1 2 at 0 °C was added methylhydrazine (0.90 mL, 16.8 mmol) dropwise. The solution was stirred at 0 °C until complete as judged by TLC, then filtered into 250 mL water. The filter caked was washed well with CH 2 C1 2 , and the aqueous layer removed. Toluene (100 mL) was added, and the mixture concentrated. Chromatography (30% EtOAc/hexane) afforded 5.1 g (61%) of a foam: R f 0.37 (30% EtOAc/hexane) ; 'H NMR (CDC1 3 ) δ 13.28 (s, IH) , 8.32 (d, 2H) , 7.75-7.35 (m, 14H) , 6.41 (t, J=6.6 Hz, IH, H-l') , 5.31 (s, 2H, ONH 2 ) , 4.39 (m, IH) , 4.11 (m, IH) , 3.51 (m, IH) , 2.43 (m, IH) , 2.07 (s, 3H, CH 3 ) , 1.89 (m, IH) , 1.09 (s, 9H) . Anal. Calcd for C 33 H 38 N 4 0 5 Si#1/4^0: C, 65.70; H, 6.43; N, 9.29. Found: C, 65.66; H, 6.35; N, 9.23. ^-benzoyl-δ' -O-tert-butyldiphenylsilyl-2' ,3' -C-dideoxy- 3' -styryl-5-methylcytidine. To a solution of 1,2,4-triazole (12.25 g, 177 mmol) in dry acetonitrile (120 mL) at 0 °C is added P0C1 3 (3.49 mL, 37.4 mmol) dropwise over 30 minutes, followed by Et 3 N (24.7 mL, 177.3 mmol) over 1 hour. A solution of 5'-0-tert- butyldiphenylsilyl-3 ' -deoxy-3 ' -C-styryl-thymidine (9.31 g, 16.4 mmol) in dry acetonitrile (50 mL) was then added dropwise at 0 °C, and the solution allowed to warm to room temperature over 4 hour, with vigorous stirring. Triethylamine (25 mL) and water (25 mL) were added and the mixture was concentrated to a small volume, diluted with EtOAc (500 mL) and extracted with 5% aqueous sodium bicarbonate (2 x 200 mL) , water (100 mL) , brine (100 mL) , then dried over magnesium sulfate, filtered and concentrated to afford 10.7 g (106%) of a foam. This material was azeotroped with dry 1,4-dioxane, then dissolved in 160 mL of the same solvent . To this solution was added a mixture of sodium hydride (2.62 g, 65.6 mmol) and benzamide (7.95 g, 65.6 mmol) stirred at room temperature for 0.5 hour via cannula in one portion. The reaction was stirred at room temperature until complete by TLC (1.5 hour) , at which point the reaction was cooled on ice, and quenched with acetic acid (3.8 mL) . The mixture was diluted 1000 mL 1:1 EtOAc/hexane, then extracted with water (2 x 500 mL) , and the organic layers dried over magnesium sulfate, filtered, concentrated, and chromatographed (50% EtOAc/hexane) afforded 8.44 g (77%) of a foam: R f 0.87 (50% EtOAc/hexane); 'H NMR (CDC1 3 ) δ 6.53 (d, J=16 Hz, IH, PhCH=) , 5.98 (dd, J=7.4, 16 Hz, IH, =CH) , 1.74 (s, 3H, CH 3 ) . i^-benzoyl-5' -O-tert-butyldiphenylsilyl-2' ,3' -dideoxy- 3' -C-formyl-5-methylcytidine. To if-Benzoyl-5' - O- tert-butyldiphenylsilyl-2' ,3' - dideoxy-3' -C-styryl-5-methylcytidine (8.4 g, 12.5 mmol) in 1,4-dioxane (300 mL) was added NaI0 4 (11.6 g, 54.3 mmol) in warm water (100 mL) . The solution was stirred vigorously, and 3.2 mL aqueous Os0 4 (4% w/w, 0.5 mmol) was added, and the reaction stirred in the dark for 4 hours. The resulting mixture was partitioned between EtOAc (900 mL) and water (500 mL) , and the resulting emulsion broken by the addition of brine. The organic layer was washed with brine, then with 5% NaS0 3 (150 mL) , then again with brine, and finally dried over magnesium sulfate, filtered, and concentrated. The residue was chromatographed (0 to 10% MeOH/CH 2 Cl 2 ) to provide 7.3 g (98%) of a foam: R f 0.65 (5% MeOH/CH 2 Cl 2 ) ; Η NMR (CDC1 3 ) δ 9.85 (s, IH, CHO) , 6.09 (t, IH, H-l'), 1.83 (s, 3H, CH 3 ) . EXAMPLE 14 Synthesis of Dimeric MMI Nucleosides HO-T*U OHβ -OH [3' -De(oxyphosphinico) -3' - (methyleneimino) thymidylyl- (3'→5') -2'-0-methyl-5-methyluridine] A mixture of 5' -0-amino-3' -0- ert-butyldiphenylsilyl-2' - 0-methyl-5-methyluridine (5.25 g, 10 mmol) and 1- [5- ( tert- butyldiphenylsilyl) -2,3-dideoxy-3-C- (formyl) S-D- erythro- pentofuranosyl] thymine (prepared according to Sanghvi et al . Synthesis, 1994, 1163) (4.92 g, 10 mmol) in CH 2 Cl 2 :ACOH (50:1 mL) was stirred at room temperature for 5 minutes. The reaction mixture was then coevaporated with toluene (3 x 50 ml) under vacuum. The reaction was complete (by TLC) by the third coevaporation. The residue was dissolved in AcOH (25 ml) and cooled to =15 °C. NaCNBH 3 (3 x 250 mg, 12 mmol) was added to the stirred reaction mixture in small portions (fume-hood) . The reaction mixture was stirred for 30 min. at =15 °C and to the cold solution aq. HCHO (30%, 5 ml) was added in one portion. The stirring was continued for 30 minutes and additional amount of NaCNBH 3 (3 x 250 mg, 12 mmol) was added in a similar manner. After 2 hours, the reaction mixture was poured into ice-water (250 ml) and extracted with CH 2 C1 2 (2 x 250 ml) . The CH 2 C1 2 layer was washed with water (2 x 250 ml) and dried MgS0 4 ) . The solvent was removed and the residue purified by silica gel column chromatography. Elution with a gradient of CH 2 Cl 2 -CH 2 Cl 2 :MeOH (95:5, v/v) provided the desired product as homogenous material. Appropriate fractions were pooled and concentrated to furnish 5.08 g (50%) of the 3', 5' -protected MMI dimer. Η NMR (CDC1 3 ) δ 1.12 (s, 18, SiMe 3 ) , 1.62 and 1.79 (2s, 6, CH 3 ) , 2.45 (s, 3, N-CH3), 2.65 (m, 2, CH 2 -N-CH 3 ) , 3.30 (s, 3, 0 CH 3 ) , 5.82 (d, 1, l'H) , 6.17 (t, 1, l'H) , 8.40 (br s, 2, NH) and other protons. To a stirred solution of 3', 5' -protected MMI dimer (2.2g, 1.88 mmol) in THF (25 ml) was added tetrabutylammonium fluoride (0.52 g, 2 mmol) at room temperature. The stirring was continued for 24 hours. The reaction mixture was loaded on the top of a silica gel column and elution with CH 2 C1 2 : MeOH (93:7, v/v) furnished homogenous material. Appropriate fractions were concentrated to furnish 1.0 g (99%) of the title compound as a white foam. 'H NMR at 60 °C (D 2 0) δ 2.26 and 2.29 (2s, 6 CH 3 ) , 2.77 (m, 2, 2' CH 2 ) , 3.10 (s, 3, N-CH 3 ) , 3.88 (s, 3, 0-CH 3 ) , 6.27 (d, 1, l'H), 6.48 (t, 1, 1' H) , 7.90 and 8.09 (2s, 2, C6H) and other protons. DMT-O-T*U 0Mβ -O-Amidite. {3' -De(oxyphosphinico) -3' - [methylene (methylimino) ] - [thymidylyl (5' -O-dimethoxytrityl) ] - (3'-»5' ) -3' -O-β-cyano- ethyldiisopropylaminophosphiryl-2' -O-methyl-5-methyluridine} The synthesis of the title phosphoramidite was accomplished in two steps from the MMI-2'-0-Me dimer (described above) in 92% overall yield. (General procedures for dimethoxytritylation and phosphitylation are described above) : Η NMR (CD 3 CN) δ 1.51 and 1.75 92s, 6, CH 3 ) , 5.85 (t, 1, l'H) , 6.10 (pseudo t, 1, l'H) 9.17 (br s, 2, NH) and other protons. 31 P (NMR) δ 150.9 and 151.2 ppm. TBDPS-0-T*T F -OH. Coupling reaction of 5' -O-amino-2 ' -fluorothymidine (0.54 g, 2 mmol) and 5' -O- ert-butyldiphenylsilyl-3 ' -deoxy-3 ' -C- formylthymidine (0.98 g, 2 mmol) according to the general procedure provided a fine, powdery solid after pouring into ice water. This material was collected, washed with water, and dried to provide 1.45 g (97%) of product which contained an impurity (ca '10%) by Η NMR. This material was used directly in the desilylation step: R f 0.44 (10 % Me0H/CH 2 Cl 2 ) ; Η NMR (CDC1 3 ) δ 6.07 (t, J=5.7 Hz, IH, H-l') , 5.75 (d, J=19.1 Hz, IH, H-l'') . TBDPS-0-T* Mθ C-0-TBDPS. Coupling reaction of 5' -0-amino-_N-benzoyl-3 ' -0- tert- butyldiphenylsilyl-5-methyl-2' -deoxycytidine (2.02 g, 3.37 mmol) and 5' -0- ert-butyldiphenylsilyl-3 ' -deoxy-3 ' -C- formylthymidine (1.66 g, 3.37 mmol) according to the general procedure provided 2.8 g (84%) of a hard foam: R f 0.50 (10 % Me0H/CH 2 Cl 2 ) ; Η NMR (CDC1 3 ) δ 6.33 (t, J=6.0 Hz, IH, H-l') , 6.08 (d, J=6.0 Hz, IH, H-l'') , 2.37 (s, 3H, NCH 3 ) , 1.80 (s, 3H, CH 3 ) , 1.59 (s, 3H, CH 3 ) . Anal. Calcd for C 54 H 68 N 6 0 8 Si 2 *2H 2 0: C, 63.50; H, 7.11; N, 8.23. Found: C, 63.51; H, 6.80; N, 8.42. TBDPS-0-A* Mβ C-0-TBDPS . Coupling reaction of 5' -O-amino-i^-benzoyl-S ' -0- tert- butyldiphenylsilyl-5-methyl-2' -deoxycytidine (1.43 g, 2.39 mmol) and 5' -O- ert-butyldiphenylsilyl-2' , 3' -dideoxy-3 ' -C- formyl adenosine (1.2 g, 2.39 mmol) according to the general procedure provided 1.26 g (53%) of a hard foam: R f 0.35 (10 % MeOH/CH 2 Cl 2 ) ; Η NMR (CDC1 3 ) δ 8.30 (s, IH) , 8.09 (s, IH) , 6.35-6.22 (m, 2H, H-l', H-l") , 5.87 (s, 2H, NH 2 ) , 2.42 (s, 3H, NCH 3 ) , 1.72 (s, 3H, CH 3 ) . Anal. Calcd for C 54 H 67 N 9 0 6 Si 2 »H 2 0 : C, 64.07; H, 6.87; N, 12.45. Found: C, 64.19; H, 6.91; N, 12.34. TBDPS-0- Mβ C*T-0-TBDPS. Coupling reaction of 5' -0-amino-3' -O- ert-butyldiphenyl- silylthymidine (5.9 g, 12 mmol) and N 4 -benzoyl-5' -O- tert- butyldiphenylsilyl-2' ,3' -dideoxy-3' -C-formyl-5-methylcytidine (7.15 g, 12 mmol) according to the general procedure provided 7.0 g (60%) of a hard foam. This material was pure by TLC and 'H NMR, and was used -directly in the next step: R f 0.58 (10% MeOH/CH 2 Cl 2 ) ; Η NMR (CDC1 3 ) δ 6.34 (t, IH, H-l'), 6.12 (t, IH, H-l"), 2.39 (s, 3H, NCH 3 ) , 1.80 (s, 3H, CH 3 ) , 1.60 (s, 3H, CH 3 ) . TBDPS-0-T* Mθ C Bz -0-TBDPS. TBDPS-0-T* e C-0-TBDPS (2.70 g, 2.75 mmol) was N- benzoylated according to the general procedure, then chromatographed (30% to 50% EtOAc/hexanes) to yield 1.80 g (60%) of a hard foam: R f 0.54 (50% EtOAc/hexanes) ; Η NMR (CDC1 3 ) δ 6.35 (t, J=7.0 Hz, IH, H-l') , 6.09 (t, J=5.9 Hz, IH, H-l"), 2.40 (s, 3H, NCH 3 ) , 1.97 (s, 3H, CH 3 ) , 1.60 (s, 3H, CH 3 ) . Anal. Calcd for C 61 H 72 N 6 O 9 Si 2 »0.5 H 2 0: C, 66.70; H, 6.70; N, 7.65. Found: C, 66.65; H, 6.55; N, 7.55. TBDPS-0- Mβ C Bz *T-0-TBDPS. TBDPS-0- Me C*T-0-TBDPS (7.0 g, 7.11 mmol) was benzoylated according to the general procedure, then chromatographed (2% MeOH/CH 2 Cl 2 ) to yield 7.7 g (100%) of a hard foam: R f 0.25 (2% MeOH/CH 2 Cl 2 ) ; Η NMR (CDC1 3 ) δ 6.35 (dd, J=1.7, 6.0 Hz, IH, H-l') , 6.12 (t, J=6.0 Hz, IH, H-l") , 2.42 (s, 3H, NCH 3 ) , 1.81 (s, 6H, 2 CH 3 's) . Anal. Calcd for C 61 H 72 N 6 0 9 Si 2 : C, 67.25; H, 6.66; N, 7.71. Found: C, 66.92; H, 6.51; N, 7.43. HO-T*T F -OH. TBDPS-0-T*T F -OH (1.30 g, 1.70 mmol) was desilylated according to the general procedure to afford 0.65 g (67%) of a hard foam: R f 0.29 (10% MeOH/CH 2 Cl 2 ) ; X H NMR (DMSO-d ff ) δ 11.44 (s, IH) , 11.26 (s, IH) , 7.82 (s, IH) , (7.52 s, IH) , 6.03 (t, J= 5.3 Hz, IH, H-l') , 5.88 (dd J=2.0 , 18.9 Hz, IH, H-l") , 5.71 (d, IH, 3"-OH) , 5.08 (t, IH, 5'-OH) , 5.12 (dm, J=74.4 Hz, IH, H-2") , 4.2-3.4 (m, 9H) , 2.72 (m, IH) , 2.59 (S, 3H, NCH 3 ) , 2.15 (m, 2H) , 1.80 (s, 3H, CH 3 ) , 1.77 (s, 3H, CH 3 ) . Anal. Calcd for C 22 H 30 N 5 O 9 F*H 2 O: C, 48.44; H, 5.91; N, 12.84. Found: C, 48.80; H, 5.92; N, 12.53. HO-T* Mβ C Bz -OH. TBDPS-0-T* Me C Bz -0-TBDPS (1.70 g, 1.56 mmol) was desilylated according to the general procedure to afford 0.85 g (89%) of a hard foam: R f 0.44 (10% MeOH/CH 2 Cl 2 ) ; Η NMR (DMSO-d 6 ) δ 13.02 (s, IH) , 11.26 (s, IH) , 8.19 (m, 2H) , (7.84 s, 2H) , 7.62-7.40 (m, 3H) , 6.15 (t, J= 6.4 Hz, IH, H-l') , 6.03 (t J=5.4 Hz, IH, H-l") , 5.38 (d, IH, 3-OH) , 5.11 (t, IH, 5-OH) , 4.38 (t, J=5.0 Hz, IH) , 4.3-3.5 (m, 8H) , 2.80-2.45 (m, 2H) , 2.61 (s, 3H, NCH 3 ) , 2.17 (m, 3H) , 2.05 (s, 3H, CH 3 ) , 1.77 (s, 3H, CH 3 ) . Anal. Calcd for C 29 H 36 N 6 O 9 »0.5 H 2 0: C, 56.03; H, 6.00; N, 13.52. Found: C, 56.18; H, 5.97; N, 13.30. HO- Mβ C Bl *T-OH. TBDPS-0- Me C Bz *T-0-TBDPS (6.97 g, 6.4 mmol) was desilylated according to the general procedure to afford 3.14 g (80%) of a hard foam: R f 0.50 (10% MeOH/CH 2 Cl 2 ) ; Η NMR (DMSO-d e ) δ 13.12 (s, IH) , 11.32 (s, IH) , (8.31 s, IH) , 8.22 (m, 2H) , 7.70-7.40 (m, 4H) , 6.16 (t, J= 6.9 Hz, IH, H-l') , 6.03 (t J=4.6 Hz, IH, H-l"), 5.32 (d, IH, 3-OH) , 5.25 (t, IH, 5-OH) , 4.30-3.60 (m, 9H) , 2.80-2.45 (m, 2H) , -2.62 (s, 3H, NCH 3 ) , 2.35-1.90 (m, 3H) , 2.04 (s, 3H, CH 3 ) , 1.80 (s, 3H, CH 3 ) . Anal. Calcd for C 29 H 36 N 6 0 9 : C, 56.86; H, 5.92; N, 13.72. Found: C, 56.48; H, 6.23; N, 13.35. DMT-0-T*T F -OH. HO-T*T F -OH (0.65 g, 1.23 mmol) was tritylated according to the general procedure to afford 0.72 g (73%) of the dimethoxytrityl ether derivative: R f 0.39 (10% MeOH/CH 2 Cl 2 + 0.1% Et 3 N) ;'H NMR (CDCl 3 ) δ 6.08 (t, J=5.4 Hz, IH, H-l') , 5.68 (d, J=19.5 Hz, IH, H-l") , 5.07 (dd J=54.0, 4.2 Hz, IH, H- 2" ) . DMT-0-T* Mβ C Bz -OH. HO-T* Me C Bz -OH (0.80 g, 1.31 mmol) was tritylated according to the general procedure to afford 0.95 g (79%) of the dimethoxytrityl ether derivative: R f 0.45 (10% MeOH/CH 2 Cl 2 + 0.1% Et 3 N) ; 'H NMR (CDC1 3 ) δ 6.21 (t, J=6.3 Hz, IH, H-l') , 6.09 (t, J=5.5 Hz, IH, H-l") . DMT-0- Mβ C Bl *T-OH. HO- Me C Bz *T-OH (1.22 g, 2.0 mmol) was tritylated according to the general procedure. The reaction was incomplete. The unreacted starting was separated from the starting material via chromatography and the unreacted starting material tritylated again according to the general procedure. The products obtained were combined to afford 1.25.g (68%) of the dimethoxytrityl ether derivative: R f 0.45 (10% MeOH/CH 2 Cl 2 + 0.1% Et 3 N) ; 'H NMR (CDCl 3 ) δ 6.20 (t, J=6.3 Hz, IH, H-l') , 6.11 (t, J=5.2 Hz, IH, H-l") . DMT-0-T*T-0-TBDPS. The MMI dimer Tr-0-T*T-0-TBDPS was prepared from Tr-O-T- I and CH 2 =NO-T-0-TBDPS via our radical coupling reaction we described in F. Debart et. al . Tetrahedron Lett . 1992, 33 , 2645) , followed by our reductive methylation of the intermediate hydroxylamine that we described in J.-J. Vasseur et. al . J. Am . Chem. Soc . 1992, 114 , 4006. This material (6.78 g, 6.8 mmol) was dissolved in MeOH (150 mL) , 0.5 N HCl in ether (2 mL) was added, and the reaction stirred at room temperature for 2 hours. Triethylamine (1.5 mL) was added, and the solution was concentrated, then chromatographed (5% MeOH/CH 2 Cl 2 ) to afford 4.25 g (83%) of the 5' -unprotected dimer (R f 0.30, 5% MeOH/CH 2 Cl 2 ) as a hard foam. This material was then dimethoxytritylated according to the general procedure to provide 5.3 g (89%) of a foam: R f 0.56 (1% MeOH/CH 2 Cl 2 ) ; Η NMR (CDC1 3 ) δ 6.31 (t, IH, H-l') , 6.10 (t, IH, H-l") , 2.35 (s, 3H, NCH 3 ) , 1.73 (s, 3H, CH 3 ) , 1.48 (s, 3H, CH 3 ) . DMT-0-T*T-OH. DMT-0-T*T-0-TBDPS (2.7 g, 2.6 mmol) was desilylated according to the general procedure, except that the crude material was chromatographed using a stepwise gradient of 0 to 4% MeOH/CH 2 Cl 2 + 0.1% Et 3 N. Concentration of the appropriate fractions provided 1.78 g (84%) of the dimethoxytrityl ether derivative: R f 0.44 (5 % MeOH/CH 2 Cl 2 + 0.1% Et 3 N) ; 'H NMR (CDCl 3 ) δ 6.22 (t, J=6.4 Hz, IH, H-l') 6.08, (t, J=5.4 Hz, IH, H-l") . DMT-0- Mβ C Bz * Mβ C Bz -0-TBDPS. To a solution of 1, 2,4-triazole (11 g, 159 mmol) in dry acetonitrile (115 mL) at 0 °C is added P0C1 3 (3.4 mL, 37 mmol) dropwise over 30 minutes, followed by Et 3 N (26 mL, 185 mmol) over 1 hour. A solution of DMT-0-T*T-0-TBDPS (2.6 g, 2.47 mmol) in dry acetonitrile (10 mL) was then added dropwise at 0 °C, and the solution allowed to warm to room temperature over 3.5 hours, with vigorous stirring. The mixture was poured into ice water (200 mL) and extracted with EtOAc (2 x 200 mL) . The combined organic layers were washed with saturated aqueous NaHC0 3 (2 x 100 mL) , water (100 mL) , and brine (100 mL) , then dried over magnesium sulfate, filtered and concentrated to afford 2.56 g (90%) of a yellow foam. This material was azeotroped with dry 1,4-dioxane, dissolved in 25 mL of the same solvent. To this solution was added a mixture of sodium hydride (0.35 g, 8.87 mmol) and benzamide (1.08 g, 8.87 mmol) stirred at room temperature for 0.5 hour via cannula in one portion. The reaction was stirred at room temperature until complete by TLC, at which point the reaction was cooled on ice, and quenched with acetic acid (0.5 mL, 8.87 mmol) . The mixture was diluted with water (200 mL) and CH 2 C1 2 (200 mL) , and the organic layers washed with water (2x200 mL) , brine, and then dried over magnesium sulfate, filtered and concentrated. Chromatography (CH 2 C1 2 + 0.1% Et 3 N) afforded 2.06 g (74%) of a foam: R f 0.95 (CH 2 C1 2 + 0.1% Et 3 N) . DMT-0- Mβ C Bz * Mβ C Bz -0H. DMT-0- Me C Bz * Me C Bz -OTBDPS (1.36 g, 1.1 mmol) was desilylated according to the general procedure, except that the column was packed with 10% hexanes/CH 2 Cl 2 + 0.1% Et 3 N, then eluted with the same solvent, follow by a stepwise gradient of 0 to 5% MeOH/CH 2 Cl 2 + 0.1% Et 3 N. Concentration of the appropriate fractions provided 0.69 g (63%) of the dimethoxytrityl ether derivative: R f 0.63 (1% MeOH/CH 2 Cl 2 + 0.1% Et 3 N) ; Η NMR (CDC1 3 ) δ 6.25-6.05 (m, 2H, H-l', H-l") . DMT-0-T*T F -0-Amidite. DMT-0-T*T F -0H (0.72 g, 0.9 mmol) was phosphitylated according to the general procedure to afford 0.79 g (85%) of the phosphoramidite derivative: R f 0.86 (EtOAc + 0.1% Et 3 N) ; 'H NMR (CD 3 CN) δ 6.09 (t, J=5.6 Hz, IH, H-l') 5.81 (d, J=18.8 Hz, IH, H-l") ; 31 P NMR (CD 3 CN) δ 151.66 (d, J=9.0 Hz), 151.35 (d, J=7.9 Hz) . DMT-0-T* Mβ C Bz -0-Amidite. DMT-0-T* Me C Bz -OH (0.94 g, 1.0 mmol) was phosphitylated according to the general procedure to afford 0.71 g (62%) of the phosphoramidite derivative: R f 0.83 (EtOAc + 0.1% Et 3 N) ; Η NMR (CD 3 CN) δ 6.20-6.05 (m, 2H, H-l', H-l") ; 31 P NMR (CD 3 CN) δ 149.65,' 149.43. DMT-0- Mβ C Bz *T-0-Amidite. DMT-0- Me C Bz *T-OH (1.17 g, 1.28 mmol) was phosphitylated according to the general procedure to afford 1.10 g (77%) of the phosphoramidite: R f 0.55 (80% EtOAc/hexanes + 0.1% Et 3 N) ; 'H NMR (CD 3 CN) δ 6.20-6.05 (m, 2H, H-l', H-l") ; 31 P NMR (CD 3 CN) δ 149.63, 149.24. DMT-0- Mβ C Bz * Mβ C Bz -0-Amidite . DMT-0- Me C Bz * Me C Bz -OH (0.30 g, 0.3 mmol) was phosphitylated according to the general procedure to afford 0.31 g (81%) of the phosphoramidite: R f 0.81 (80% EtOAc/hexanes + 0.1% Et 3 N) ; 'H NMR ( CD 3 CN) δ 6 . 20 - 6 . 05 (m, 2H, H- l ' , H- l " ) ; 31 P NMR ( CD 3 CN) δ 149 . 70 , 149 . 45 . DMT-0-T*T-0-Amidite . DMT-0-T*T-OH (1.78 g, 2.19 mmol) was phosphitylated according to the general procedure, except that the organic layer was extracted with 5% aqueous sodium bicarbonate, dried, filtered, and concentrated prior to chromatography (1% MeOH/CH 2 Cl 2 + 0.1% Et 3 N) . This resulted in contamination with an impurity, and additional chromatography (1:1 CH 2 Cl 2 /EtOAc + 0.1% Et 3 N to 2% MeOH in 1:1 CH 2 Cl 2 /EtOAc + 0.1% Et 3 N) was necessary to completely purify the product. Fractions containing only pure product were pooled, concentrated, and lyophilized from 1,4-dioxane to afford 1.28 g (58%) of the phosphoramidite derivative: R f 0.91 (5% MeOH/CH 2 Cl 2 + 0.1% Et 3 N) ; *H NMR (CD 3 CN) δ 6.20-6.05 (m, 2H, H-l', H-l") ; 31 P NMR (CD 3 CN) δ 149.59, 149.23. EXAMPLE 15 Incorporation Of MMI Dimers And Assembly of Chimeric Oligonucleotides Methylene (methyl) imino (MMI) linked chimeric oligonucleotides correspond to oligonucleotides where one or several phosphodiesters and/or phosphorothioates linkages have been replaced by MMI internucleosidic linkage. Thus, creating an alternating motif of MMI→P=0→MMI or MMI→P=S→MMI linked chimeric oligomers. The chimeric oligonucleotides containing MMI dimers were synthesized utilizing standard phosphoramidite chemistry. In this case the chimeric oligomers were synthesized attached to CPG (Controlled Pore Glass) solid support and the assembling was performed on an automated DNA synthesizer such as Millipore Expedite or Applied Biosystem 380B. MMI dimers synthesized as phosphoramidite elongation units (DMT-X*X- phosphoramidite, X = A, T, G, C, 5MeC, * = 3' -CH 2 -N(CH 3 ) -0-5' or X*X MMI) were obtained according the procedure described above in the Example 14. The initial deoxynucleoside or MMI dimer determining the 3'-end of the MMI containing chimeric oligonucleotide was loaded on to the CPG solid support via a succinyl linkage following the procedure described in Example 2 above. For example: 5' -0-DMTr-T*C-0- (succinyl-CPG-NMe 2 ) -3' was loaded onto the CPG providing a loading of 24.20 mmole/g and 5'-0-DMTr- Me C Bz * Me C Bz -0- (succinyl-CPG-NMe 2 ) -3' was loaded onto the CPG providing a loading of 22.32 mmole/g. Protocol For The Incorporation Of the MMI Dimers Into Oligomers Step 1 - Detritylation: 1 mmole of 5' -0-DMT-O- (succinyl-CPG-NMe 2 ) -3 ' MMI dimer was packed into a small column and connected in line to a Millipore Expedite DNA synthesizer. TCA (3%) solution was passed through the column according the standard protocol used for standard amidite chemistry. Step 2 - Coupling (Of MMI Phosphoramidite Dimers) : MMI phosphoramidite dimers were diluted in anhydrous acetonitrile up to a concentration of 0.0673 Mol/1. Using the standard coupling step 0.217 ml of a mixture of MMI dimer solution and lH-tetrazole (l/l, v/v) was passed through the column with an extended coupling wait step of 300 seconds. Step 3 - Oxidation or Sulfurization of the phosphite triester linkage: This step was carried out using the standard oxidizing protocol required for the commercial deoxyribonucleoside phosphoramidites. Step 4 - Capping: This step was carried out using the standard capping protocol required for commercial deoxyribonucleoside phosphoramidites. Step 5- Isolation And Purification: At the end of the automated synthesis, MMI containing oligonucleotides were concomitantly deprotected and cleaved from the solid support by treatment with concentrated aqueous ammonia solution (30%) at 55 °C for 10 hours. The ammonia solution was then evaporated and the full length oligonucleotides were separated from the failure sequences on reverse phase HPLC (column: RCM Waters 8 X 10 Bondapack HC18HA, flow rate 2 ml/minutes, gradient 5% to 25% CH,CN in TEAA 0.05 N pH 7.00 over 25 minutes) . Table 2: Chimeric Oligomers Containing MMI Linkages (Denoted by *) Analytical Data For Oligomers In Table 2 Column Supelco LC 18 15cm x 4.6mm, 5mm, 5% to 25 CH,CN in 0.05M TEAA, pH 7.00 over 25 minutes, 1ml/minute. Table 3 : Chimeric Oligomers Containing T* 2 ,. 0Mβ T MMI dimers Analytical Data For Oligomers In Table 3 Column Supelco LC 18 15cm x 4.6mm, 5mm, 5% to 25 % CH 3 CN in 0.05M TEAA, pH 7.00 over 25 minutes, lml/minute. Table 4 : Chimeric Oligomers Containing T* 2 ,. P T MMI dimers Analytical Data For Oligomers In Table 4 Column Supelco LC 18 15cm x 4.6mm, 5mm, 5% to 25' CH 3 CN m 0.05M TEAA, pH 7.00 over 25 minutes, lml/minute. EXAMPLE 16 Post-Oligo modifications (Regiospecific Reductive Alkylation Of Imino Linkage After Chimeric Oligomer Synthesis) General Procedure The key feature of this procedure is to utilize the oximes dimers (prepared according to our published procedure in J " . Am . Chem . Soc . 1992, 114 , 4006) as their phosphoramidites and incorporate into oligomers as described above. For illustrative purposes, we describe two of such oxime dimers (DMT-0-T*T- phosphoramidite * = 3'-CH=N-0-5' or abbreviated as T*T oxime and DMT-0-T*G iBu phosphoramidite * = 3'-CH=N-0-5' or abbreviated as T*G oxime) as phosphoramidites and incorporated into various oligomers (see Tables 5-8 for examples) . The automated assembly of chimeric oligomers containing oxime linked dimers was performed on a Millipore Expedite DNA synthesizer using previously described methodology (see Example 15 for details) . After deprotection and purification of the oxime containing chimeric oligonucleotides, all of the oximes linkages were selectively reduced and alkylated according the protocol described below. The following procedure was carried out in a small flask (2 mL) : 1) - Oxime containing oligonucleotide (1 μmole) was dissolved in 0.23 mL water 2) - Diluted with MeOH 0.5 mL 3) - Bromocresol Green solution was added in water 15 ml 4) - NaBH 3 CN (40 mg) was added 5) - HCl/MeOH 2N solution (0.1 ml) was added 6) - Mixture was vortexed for 5 minutes 7) - Repeat steps 5 and 6 once 8) - Add the desired aldehyde (R-CHO) 100 eq/secondary imino linkage 9) - Vortex for 30 minutes 10) - Add NaBH 3 CN 40mg 11) - Add 0.1 mL HCl/MeOH 2N solution 12) - Vortex for 2 minutes 13) - Repeat steps 11 and 12 six times 14) - Neutralization with triethylammonium acetate 2N solution in water 0.3 mL The solution was evaporated and the residue loaded on a Sephadex G-25 desalting column. Elution with water, pooling of appropriate fractions and evaporation furnished the desired oligonucleotides. Purification by reverse phase HPLC (column: RCM Waters 8 X 10 B ndapack HC18HA, flow rate 2 mL/minutes, gradient: 5% → 25% CH3CN in TEAA 0.05 N pH 7.00 over 25 minutes) gave analytically pure chimeric oligomers. Table 5. Chimeric Oligomers Prepared Via Post-Oligo Modification Method Containing MMI Linkages Column Supelco LC 18 15cm x 4.6mm, 5mm, 5% to 25% CH 3 CN in 0.05M TEAA, pH 7.00 over 25 minutes, lml/minute. Table 6. Chimeric Oligomers Prepared Via Post-Oligo Modification Method Containing MEI [methylene(ethylimino) ] Linkages Column Supelco LC 18 15cm x 4.6mm, 5mm, 5% to 25% CH 3 CN in 0.05M TEAA, pH 7.00 over 25 minutes, lml/minute. Table 7. Chimeric Oligomers Prepared Via Post-Oligo Modification Method Containing MPI [methylene(propylimino) ] Linkages Column Supelco LC 18 15cm x 4.6mm, 5mm, 5% to 25% CH 3 CN in 0.05M TEAA, pH 7.00 over 25 minutes, lml/minute. Table 8. Chimeric Oligomers Prepared Via Post-Oligo Modification Method Containing McPI [methylene(eyelopropylimino) ] Linkages ID No . Sequence 11045 G P0 Cp 0 G PS T*T P0 T*T P0 T*T P0 T*T P0 T*T P0 G P0 C P0 G- 3 ' McPI 12 Phosphodiesters + 5 McPI Linkages Column Supelco LC 18 15cm x 4.6mm, 5mm, 5% to 25% CH 3 CN in 0.05M TEAA, pH 7.00 pver 25 minutes, lml/minute. EXAMPLE 17 Preparation of Dimeric MMI Nucleosides Incoporating Methylene(aralkylimido) Linkages 5' - O - ert-Butyldiphenylsilyl-3 ' -de (oxyphosphinico) -3 ' - [methylene (l-butyl-4- (1-pyrenyl) imino) ] thymidylyl- (3'-* 5') -3'- O-tert-butyldiphenylsilylthymidine. To an oven-dried 200 mL recovery flask was added 3.51g (3.05 mmols) of 5 ' - O- ert-butyldiphenylsilyl-3 ' - de (oxyphosphinico) -3' -methyleneiminothymidylyl- (3'→ 5' ) -3 ' - O- tert-butylsilylthymidine and l-pyrenebutan-4-al (1.05 g, 3.85 mmols) were added as solids in one portion. The mixture was taken up in 20 mL of anhydrous CH 2 C1 2 and 80 mL of anhydrous toluene was added along with 1.0 mL of glacial AcOH yielding a pale golden solution. The mixture was evaporated on a rotary evaporator to a thick syrup. The syrup was then redissolved in CH 2 C1 2 , rediluted with toluene and acetic acid, then evaporated three additional times at which point TLC analysis on silica gel (19:1 CH 2 Cl 2 /MeOH) showed the complete consumption of dimeric starting material . The flask containing the mixture was then equipped with a magnetic stir bar, a rubber septum, and an argon inlet and dissolved in 7.5 mL CH 2 C1 2 and diluted with 7.5 mL MeOH. Bromocresol green indicator solution in MeOH was added dropwise to give a more notable yellow color to the solution and a catalytic amount of AcOH was also added at this time. The mixture was then equilibrated in an ice water bath. At ice bath temperature, NaCNBH 3 (0.850 g, 13.52 mmol) was added in four approximately equal portions over a period of 4 h. Over this time, HOAc was added dropwise upon the appearance of blue-green color to restore the original gold-yellow tint and maintain the pH of the mixture. After the final addition, the mixture was allowed to stir 2 additional hours at ice bath temperature. The mixture was then partitioned between water and CH 2 C1 2 . The aqueous phase was extracted 3 additional times with CH 2 C1 2 and the combined organic phase was washed successively with saturated NaHC0 3 , water, and brine and then dried over anh. Na 2 S0 4 . The solution was decanted from the solids, evaporated and chromatographed on silica using 98:2 CH 2 Cl 2 /MeOH to yield 3.241 g of the title compound as a ivory foam. Further transformations of this compound ( e . g. bis desilylation, 5' -dimethoxytritylation, and 3' -O-β-cyanoethyl- (N,N-diisopropylamino)phosphydylation) were carried out as described for the methyl (methyleneimino) analogs above. The compounds were characterized by 4ϊ and 13 C NMR at either 200 or 400 MHZ. The final phosphoramidite product showed the expected two diastereotopic resonances in the 31 P spectrum at 148.21 ppm and 147.11 ppm, respectively. 5' -O-tert-Butyldiphenylsilyl-3 ' -de (oxyphosphinico) -3 ' - [methylene- (l-propyl-3-l-pyrenylimino) ] thymidylyl- (3'-»5' ) -3' - O-ter -butyldiphenylsilylthymidine. To an oven-dried 50 mL round bottom flask equipped with a septum, positive pressure argon line and magnetic stirbar was added 1.08 g (1.12 mmols) of 5' - 0- ert-butyldiphenylsilyl-3' - de (oxyphos-phinico) -3' -methyleneiminothymidylyl- (3'→5' ) -3' -0- tert-butylsilylthymidine as a solid. The dimer was taken up in 3 mL of anhydrous CH 2 C1 2 and 3 mL of anhydrous MeOH was added yielding a pale golden solution. 5 drops of bromocresol green was added followed by glacial AcOH dropwise until the solution retained a yellow coloration beyond the initial color of the solution. l-pyrenepropan-3-al (0.5783 g, 2.239 mmols) was added as a solid in one portion with stirring. The mixture was then allowed to stir at ambient temperature lh under argon after which time it was equilibrated in an ice-water bath. At ice bath temperature, NaCNBH 3 (0.282 g, 4.48 mmol) was added in four approximately equal portions over a period of 4 h. Over this time, HOAc was added dropwise upon the appearance of blue- green color to maintain the pH of the mixture. After the final addition, the mixture was allowed to stir 2 additional hours at ice bath temperature. The mixture was then partitioned between water and CH 2 C1 2 . The aqueous phase was extracted 3 additional times with CH 2 Cl 2 and the combined organic phase was washed successively with saturated NaHC0 3 , water, and brine and then dried over anh. Na 2 S0 4 . The solution was decanted from the solids, evaporated and chromatographed on silica using 98:2 CH 2 Cl 2 /MeOH to yield 0.961 g of the title compound as a white foam. Further transformations of this compound ( e . g. bis desilylation, 5' -dimethoxytritylation, and 3' -O-β-cyanoethyl- (N,N-diisopropylamino)phosphydylation) were carried out as described for the methyl (methyleneimino) analogs above. The compounds in this sequence were characterized by ~~ E and 13 C NMR at either 200 or 400 MHZ. The final phosphoramidite product showed the expected two diastereotopic resonances in the 31 P spectrum at 149.59 ppm and 149.03 ppm, respectively. EXAMPLE 18 Incorporation of Dimeric MMI Nucleosides Having Methylene- (aralkylimido) Linkages in Oligomers The propypyreneyl T-T dimer of Example 17 was incorporated into a oligomer of the sequence Gp 0 G po Ap 0 T*Tp 0 Gp 0 Gp 0 Tp 0 C in a lOμmol synthesis using the standard protocols above. The oligomer was characterized by NMR and mass spectra. MS (Electrospray) , M + H = 3704.44. The oligomer was further shown by CGE to be full length material free of short mer sequences. EVALUATION PROCEDURE 1 - Nuclease Resistance A. Evaluation of the resistance of oligonucleotide- mimicking macromolecules to serum and cytoplasmic nucleases. Oligonucleotide-mimicking macromolecules of the invention can be assessed for their resistance to serum nucleases by incubation of the oligonucleotide-mimicking macromolecules in media containing various concentrations of fetal calf serum or adult human serum. Labelled oligonucleotide-mimicking macromolecules are incubated for various times, treated with protease K and then analyzed by gel electrophoresis on 20% polyacrylamine-urea denaturing gels and subsequent autoradiography. Autoradiograms are quantitated by laser densitometry. Based upon the location of the modified linkage and the known length of the oligonucleotide-mimicking macromolecules it is possible to determine the effect on nuclease degradation by the particular modification. For the cytoplasmic nucleases, an HL 60 cell line can be used. A post-mitochondrial supernatant is prepared by differential centrifugation and the labelled macromolecules are incubated in this supernatant for various times. Following the incubation, macromolecules are assessed for degradation as outlined above for serum nucleolytic degradation. Autoradiography results are quantitated for evaluation of the macromolecules of the invention. It is expected that the macromolecules will be completely resistant to serum and cytoplasmic nucleases. B. Evaluation of the resistance of oligonucleotide- mimicking macromolecules to specific endo- and exo-nucle- ases. Evaluation of the resistance of natural oligonucleotides and oligonucleotide-mimicking macromolecules of the invention to specific nucleases (i.e., endonucleases, 3',5'-exo-, and 5' , 3' -exonucleases) can be done to determine the exact effect of the macromolecule linkage on degradation. The oligonucleotide-mimicking macromolecules are incubated in defined reaction buffers specific for various selected nucleases. Following treatment of the products with protease K, urea is added and analysis on 20% polyacrylamide gels containing urea is done. Gel products are visualized by staining with Stains All reagent (Sigma Chemical Co.) . Laser densitometry is used to quantitate the extent of degradation. The effects of the macromolecules linkage are determined for specific nucleases and compared with the results obtained from the serum and cytoplasmic systems. As with the serum and cytoplasmic nucleases, it is expected that the oligonucleotide- mimicking macromolecules of the invention will be completely resistant to endo- and exo-nucleases. PROCEDURE 2 - 5-Lipoxygenase Analysis and Assays A. Therapeutics For therapeutic use, an animal suspected ' of having a disease characterized by excessive or abnormal supply of 5-lipoxygenase is treated by administering the macromolecule of the invention. Persons of ordinary skill can easily determine optimum dosages, dosing methodologies and repetition rates. Such treatment is generally continued until either a cure is effected or a diminution in the diseased state is achieved. Long term treatment is likely for some diseases. B. Research Reagents The oligonucleotide-mimicking macromolecules of this invention will also be useful as research reagents when used to cleave or otherwise modulate 5-lipoxygenase mRNA in crude cell lysates or in partially purified or wholly purified RNA preparations. This application of the invention is accomplished, for example, by lysing cells by standard methods, optimally extracting the RNA and then treating it with a composition at concentrations ranging, for instance, from about 100 to about 500 ng per 10 Mg of total RNA in a buffer consisting, for, example, of 50 mm phosphate, pH ranging from about 4-10 at a temperature from about 30° to about 50° C. The cleaved 5-lipoxygenase RNA can be analyzed by agarose gel electrophoresis and hybridization with radiolabeled DNA probes or by other standard methods. C. Diagnostics The oligonucleotide-mimicking macromolecules of the invention will also be useful in diagnostic applications, particularly for the determination of the expression of specific mRNA species in various tissues or the expression of abnormal or mutant RNA species. In this example, while the macromolecules target a abnormal mRNA by being designed complementary to the abnormal sequence, they would not hybridize to normal mRNA. Tissue samples can be homogenized, and RNA extracted by standard methods. The crude homogenate or extract can be treated for example to effect cleavage of the target RNA. The product can then be hybridized to a solid support which contains a bound oligonucleotide complementary to a region on the 5' side of the cleavage site. Both the normal and abnormal 5' region of the mRNA would bind to the solid support. The 3' region of the abnormal RNA, which is cleaved, would not be bound to the support and therefore would be separated from the normal mRNA. Targeted mRNA species for modulation relates to 5- lipoxygenase; however, persons of ordinary skill in the art will appreciate that the present invention is not so limited and it is generally applicable. The inhibition or modulation of production of the enzyme 5-lipoxygenase is expected to have significant therapeutic benefits in the treatment of disease. In order to assess the effectiveness of the compositions, an assay or series of assays is required. D. In Vitro Assays The cellular assays for 5-lipoxygenase preferably use the human promyelocytic leukemia cell line HL-60. These cells can be induced to differentiate into either a monocyte like cell or neutrophil like cell by various known agents. Treatment of the cells with 1.3% dimethyl sulfoxide, DMSO, is known to promote differentiation of the cells into neutrophils. It has now been found that basal HL-60 cells do not synthesize detectable levels of 5-lipoxygenase protein or secrete leukotrienes (a downstream product of 5-lipoxygenase) . Differentiation of the cells with DMSO causes an appearance of 5-lipoxygenase protein and leukotriene biosynthesis 48 hours after addition of DMSO. Thus induction of 5-lipoxygenase protein synthesis can be utilized as a test system for analysis of oligonucleotide- mimicking macromolecules which interfere with 5-lipoxygenase synthesis in these cells. A second test system for oligonucleotide-mimicking macromolecules makes use of the fact that 5-lipoxygenase is a "suicide" enzyme in that it inactivates itself upon reacting with substrate. Treatment of differentiated HL-60 or other cells expressing 5 lipoxygenase, with 10 μM A23187, a calcium ionophore, promotes translocation of 5-lipoxygenase from the cytosol to the membrane with subsequent activation of the enzyme. Following activation and several rounds of catalysis, the enzyme becomes catalytically inactive. Thus, treatment of the cells with calcium ionophore inactivates endogenous 5- lipoxygenase. It takes the cells approximately 24 hours to recover from A23187 treatment as measured by their ability to synthesize leukotriene B 4 . Macromolecules directed against 5- lipoxygenase can be tested for activity in two HL-60 model systems using the following quantitative assays. The assays are described from the most direct measurement of inhibition of 5-lipoxygenase protein synthesis in intact cells to more downstream events such as measurement of 5-lipoxygenase activity in intact cells. A direct effect which oligonucleotide-mimicking macromolecules can exert on intact cells and which can be easily be quantitated is specific inhibition of 5-lipoxygenase protein synthesis. To perform this technique, cells can be labelled with 35 S-methionine (50 μCi/mL) for 2 hours at 37° C to label newly synthesized protein. Cells are extracted to solubilize total cellular proteins and 5-lipoxygenase is immunoprecipitated with 5-lipoxygenase antibody followed by elution from protein A Sepharose beads. The immunoprecipitated proteins are resolved by SDS-polyacrylamide gel electrophoresis and exposed for autoradiography. The amount of immunopre¬ cipitated 5-lipoxygenase is quantitated by scanning densitometry. A predicted result from these experiments would be as follows. The amount of 5-lipoxygenase protein immuno- precipitated from control cells would be normalized to 100%. Treatment of the cells with 1 μM, 10 μM, and 30 μM of the macromolecules of the invention for 48 hours would reduce immunoprecipitated 5-lipoxygenase by 5%, 25% and 75% of control, respectively. Measurement of 5-lipoxygenase enzyme activity in cellular homogenates could also be used to quantitate the amount of enzyme present which is capable of synthesizing leukotrienes. A radiometric assay has now been developed for quantitating 5- lipoxygenase enzyme activity in cell homogenates using reverse phase HPLC. Cells ' are broken by sonication in a buffer containing protease inhibitors and EDTA. The cell homogenate is centrifuged at 10,000 x g for 30 min and the supernatants analyzed for 5-lipoxygenase activity. Cytosolic proteins are incubated with 10 μM 14 C-arachidonic acid, 2mM ATP, 50 μM free calcium, 100 μg/ml phosphatidylcholine, and 50 mM bis-Tris buffer, pH 7.0, for 5 min at 37° C. The reactions are quenched by the addition of an equal volume of acetone and the fatty acids extracted with ethyl acetate. The substrate and reaction products are separated by reverse phase HPLC on a Novapak C18 column (Waters Inc., Millford, MA) . Radioactive peaks are detected by a Beckman model 171 radiochromatography detector. The amount of arachidonic acid converted into di-HETE's and mono-HETE's is used as a measure of 5-lipoxygenase activity. A predicted result for treatment of DMSO differentiated HL-60 cells for 72 hours with effective the macromolecules of the invention at 1 μM, 10 μM, and 30 μM would be as follows. ' Control cells oxidize 200 pmol arachidonic acid/ 5 min/ 10 6 cells. Cells treated with 1 μM, 10 μM, and 30 μM of an effective oligonucleotide-mimicking macromolecule would oxidize 195 pmol, 140 pmol, and 60 pmol of arachidonic acid/ 5 min/ 10 s cells respectively. A quantitative competitive enzyme linked immunosorbant assay (ELISA) for the measurement of total 5-lipoxygenase protein in cells has been developed. Human 5-lipoxygenase expressed in E. coli and purified by extraction, Q-Sepharose, hydroxyapatite, and reverse phase HPLC is used as a standard and as the primary antigen to coat microtiter plates. 25 ng of purified 5-lipoxygenase is bound to the microtiter plates overnight at 4°C. The wells are blocked for 90 min with 5% goat serum diluted in 20 mM Tris-HCL buffer, pH 7.4, in the presence of 150 mM NaCl (TBS) . Cell extracts (0.2% Triton X- 100, 12,000 x g for 30 min.) or purified 5-lipoxygenase were incubated with a 1:4000 dilution of 5-lipoxygenase polyclonal antibody in a total volume of 100 μL in the microtiter wells for 90 min. The antibodies are prepared by immunizing rabbits with purified human recombinant 5-lipoxygenase. The wells are washed with TBS containing 0.05% tween 20 (TBST) , then incubated with 100 μL of a 1:1000 dilution of peroxidase conjugated goat anti-rabbit IgG (Cappel Laboratories, Malvern, PA) for 60 min at 25°C. The wells are washed with TBST and the amount of peroxidase labelled second antibody determined by development with tetramethylbenzidine. Predicted results from such an assay using a 30 mer oligonucleotide-mimicking macromolecule at 1 μM, 10 μM, and 30 μM would be 30 ng, 18 ng and 5 ng of 5-lipoxygenase per 10 6 cells, respectively with untreated cells containing about 34 ng 5-1ipoxygenase. A net effect of inhibition of 5-lipoxygenase biosynthesis is a diminution in the quantities of leukotrienes released from stimulated cells. DMSO-differentiated HL-60 cells release leukotriene B4 upon stimulation with the calcium ionophore A23187. Leukotriene B4 released into the cell medium can be quantitated by radioimmunoassay using commercially available diagnostic kits (New England Nuclear, Boston, MA) . Leukotriene B4 production can be detected in HL-60 cells 48 hours following addition of DMSO to differentiate the cells into a neutrophil- like cell. Cells (2 x 10 5 cells/mL) will be treated with increasing concentrations of the macromolecule for 48-72 hours in the presence of 1.3% DMSO. The cells are washed and resuspended at a concentration of 2 x 10 6 cell/mL in Dulbecco's phosphate buffered saline containing 1% delipidated bovine serum albumin. Cells are stimulated with 10 μM calcium ionophore A23187 for 15 min and the quantity of LTB4 produced from 5 x 10 5 cell determined by radioimmunoassay as described by the manufacturer. Using this assay the following results would likely be obtained with an oligonucleotide-mimicking macromolecule directed to the 5-LO mRNA. Cells will be treated for 72 hours with either 1 μM, 10 μM or 30 μM of the macromolecule in the presence of 1.3% DMSO. The quantity of LTB 4 produced from 5 x 10 5 cells would be expected to be about 75 pg, 50 pg, and 35 pg, respectively with untreated differentiated cells producing 75 pg LTB 4 . E. In Vivo Assay Inhibition of the production of 5-lipoxygenase in the mouse can be demonstrated in accordance with the following protocol. Topical application of arachidonic acid results in the rapid production of leukotriene B 4 , leukotriene C 4 and prostaglandin E 2 in the skin followed by edema and cellular infiltration. Certain inhibitors of 5-lipoxygenase have been known to exhibit activity in this assay. For the assay, 2 mg of arachidonic acid is applied to a mouse ear with the contralateral ear serving as a control. The polymorphonuclear cell infiltrate is assayed by myeloperoxidase activity in homogenates taken from a biopsy 1 hour following the administration of arachidonic acid. The edematous response is quantitated by measurement of ear thickness and wet weight of a punch biopsy. Measurement of leukotriene B 4 produced in biopsy specimens is performed as a direct measurement of 5- lipoxygenase activity in the tissue. Oligonucleotide-mimicking macromolecules will be applied topically to both ears 12 to 24 hours prior to administration of arachidonic acid to allow optimal activity of the compounds. Both ears are pretreated for 24 hours with either 0.1 μmol, 0.3 μmol, or 1.0 μmol of the macromolecule prior to challenge with arachidonic acid. Values are expressed as the mean for three animals per concentration. Inhibition of polymorphonuclear cell infiltration for 0.1 μmol, 0.3 μmol, and 1 μmol is expected to be about 10%, 75% and 92% of control activity, respectively. Inhibition of edema is expected to be about 3%, 58% and 90%, respectively while inhibition of leukotriene B 4 production would be expected to be about 15%, 79% and 99%, respectively. PROCEDURE 3 - Solid Support Biochemistry Reagents Oligomers of the present invention also can advantageously be used as solid-phase biochemistry reagents ( see, e . g. , "Solid-Phase Biochemistry - Analytical and Synthetic Aspects" , W. H. Scouten, ed. , John Wiley & Sons, New York, 1983) , notably in solid-phase biosystems, especially bioassays or solid-phase techniques which concerns diagnostic detection/quantitation or affinity purification of complementary nucleic acids ( see, e. g. , "Affinity Chromatography - A Practical Approach" , P. D. G. Dean, W. S. Johnson and F. A. Middle, eds., IRL Press Ltd., Oxford 1986; "Nucleic Acid Hybridization - A Practical Approach" , B. D. Harnes and S. J. Higgins, IRL Press Ltd., Oxford 1987) . Present day methods for performing such bioassays or purification techniques almost exclusively utilize "normal" oligonucleotides either physically adsorbed or bound through a substantially permanent covalent anchoring linkage to beaded solid supports such as cellulose, glass beads, including those with controlled porosity (Mizutani, et al . , J. Chromatogr. , 1986, 356, 202), "Sephadex", "Sepharose", agarose, polyacrylamide, porous particulate alumina, hydroxyalkyl methacrylate gels, diol-bonded silica, porous ceramics, or contiguous materials such as filter discs of nylon and nitrocellulose. In one example employing the chemical synthesis of MMI containing oligo-dT on cellulose beads, affinity isolation of poly A tail containing mRNA is effected (Gilham in "Methods in Enzymology , " L. Grossmann and K. Moldave, eds., vol. 21, part D, page 191, Academic Press, New York and London, 1971) . All the above-mentioned methods are applicable, however, it is especially desirable to utilize covalent linkage over the physical adsorption of the molecules in question, since the latter approach has the disadvantage that some of the immobilized molecules can be washed out (desorbed) during the hybridization or affinity process. Further, certain types of studies concerning the use of the oligomers of the invention in solid-phase biochemistry can be approached, facilitated, or greatly accelerated by use of the recently-reported "light- directed, spatially addressable, parallel chemical synthesis" technology (Fodor, et al . , Science, 1991, 251 , 161 ) , a technique that combines solid-phase chemistry and photolithography to produce thousands of highly diverse, but identifiable, permanently immobilized compounds in a substantially simultaneous way. PROCEDURE 4 - Investigation of mutant β-amyloid precursor protein (βAPP) Point mutations in the gene encoding β-amyloid have been suggested in familial Alzheimer's disease (FAD) . To analysis samples of individual biological cellular material, MMI oligomers are used to probe for such point mutation expressed proteins. A MMI containing oligomer of the selected sequence coding for the protein of interest is synthesized as above. Upon completion of the oligomer sequence and prior to removal of the oligomer from the solid support, a fluorescein label is added to the oligomer using fluorescein phosphoramidite (Cat. No. 10-1963-95, Glen Research Corp., Sterling VA) . This amidite is attached in the normal manner as the last phosphate residue added. Alternatively, the oligomers can be labeled with other reporter molecules (acridine or psoralen, both also available from Glen Research or rhodamine) before or after oligomer synthesis. Labeled oligomers are contacted with tissue or cell samples suspected of abnormal βAPP expression under conditions in which specific hybridization can occur, and the sample is washed to remove unbound oligomers. Label remaining in the sample indicates bound oligonucleotide and is quantitated using a fluorimeter, fluorescence microscope or other routine means. Tissue or cell samples suspected of expressing a point mutation in the βAPP gene are incubated with a fluorescein- labeled oligomer which is targeted to the mutant codon 717, codon 670 or codon 671 of βAPP mRNA. An identical sample of cells or tissues is incubated with a second labeled oligomer which is targeted to the same region of normal βAPP mRNA, under conditions in which specific hybridization can occur, and the sample is washed to remove unbound oligomer. Label remaining in the sample indicates bound oligomer and can be quantitated using a fluorimeter or other routine means. The presence of mutant βAPP is indicated if the first sample binds labeled oligomer and the second sample does not bind fluorescent label. Double labeling can also be used with the oligomers to specifically detect expression of mutant βAPP. A single tissue sample is incubated with a rhodamine-labeled oligomer which is targeted to codon 717, codon 670 or codon 671 of mutant βAPP mRNA and a fluorescein-labeled oligomer which is targeted to the translation initiation site of mutant βAPP mRNA, under conditions in which specific hybridization can occur. The sample is washed to remove unbound oligomer and labels are detected by and fluori etry with appropriate filters. The presence of mutant βAPP is indicated if the sample does not bind rhodamine-labeled oligomer but does retain the fluorescein label. PROCEDURE 5 - Detection of mutant H-ras gene expression Point mutations in the H-ras gene have been implicated in numerous aberrations of the Ras pathway. MMI oligomers are labeled after synthesis with fluorescein or other fluorescent tag as illustrated above. Alternatively, the oligomers are labeled with other reporter molecules before or after oligomer synthesis. Labeled oligomers are contacted with tissue or cell samples suspected of abnormal ras expression under conditions in which specific hybridization can occur, and the sample is washed to remove unbound oligomer. Label remaining in the sample indicates bound oligomer and is quantitated using a fluorimeter, fluorescence microscope or other routine means. Tissue or cell samples suspected of expressing a point mutation in the H-ras gene are incubated with a fluorescein- labeled oligomer which is targeted to the mutant codon 12, codon 13 or codon 61 of H-ras mRNA. An identical sample of cells or tissues is incubated with a second labeled oligomer which is targeted to the same region of normal H-ras mRNA, under conditions in which specific hybridization can occur, and the sample is washed to remove unbound oligomer. Label remaining in the sample indicates bound oligomer and can be quantitated using a fluorimeter or other routine means . The presence of mutant H-ras is indicated if the first sample binds labeled oligomer and the second sample does not bind fluorescent label. Double labeling can also be used with oligomers to specifically detect expression of mutant ras. A single tissue sample is incubated with a rhodamine-labeled oligomer which is targeted to codon 12, codon 13 or codon 61 of mutant H-ras mRNA and a fluorescein-labeled oligomer which is targeted to the translation initiation site of ras mRNA, under conditions in which specific hybridization can occur. The sample is washed to remove unbound oligomer and labels are detected by and fluorimetry with appropriate filters. The presence of mutant ras is indicated if the sample does not bind rhodamine-labeled oligomer but does retain the fluorescein label . PROCEDURE 6 - Effect of MMI-containing antisense oligonucleotides on PKC-α mRNA levels: A549 cells were treated with compounds ID No.s 9495 and 9496 as well as a phosphorothioate oligonucleotide standard of the same sequence as compound ID No. 9495 above, at doses from 100 to 400 nM for four hours in the presence of the cationic lipids DOTMA/DOPE, washed and allowed to recover for an additional 20 hours. Total RNA was extracted and 20μg of each was resolved on 1.2% gels and transferred to nylon membranes. These blots were probed with a 32 P radiolabeled PKC-α cDNA probe and then stripped and reprobed with a radiolabeled G3PDH probe to confirm equal RNA loading. PKC-α transcripts were examined and quantified with a Phosphorlmager (Molecular Dynamics, Sunnyvale CA) . The results indicate that oligonucleotides of seqences 9495 and 9496 gave approximately 75% reduction of PKC- a mRNA levels, with IC 50 s of approximately 80 nM and 120 nM, respectively. The phosphorothioate oligonucleotide standard, known to be active against PKC-α, had an IC 50 in this assay of approximately 175 nM. Thus the MMI compounds exhibited greater activity than the test standard. The high specific binding of the test compounds to the PKC-α sequence can also be used to distinguish PKC-α mRNA from other mRNA of other PKC isozymes such as the β, T and η isozymes. PROCEDURE 7 - Northern blot analysis of ras expression in vivo Cells were treated with oligomers in Opti-MEM reduced- serum medium containing 2.5 μl DOTMA. Oligomer was then added to the desired concentration. After 4 hours of treatment, the medium was replaced with medium without oligonucleotide. Cells were harvested 48 hours after oligomer treatment and RNA was isolated using a standard CsCl purification method. Kingston, R.E., in Current Protocols in Molecular Biology, (F.M. Ausubel, R. Brent, R.E. Kingston, D.D. Moore, J.A. Smith, J.G. Seidman and K. Strahl, eds.), John Wiley and Sons, NY. Northern hybridization: 10 μg of each RNA was electrophoresed on a 1.2% agarose/formaldehyde gel and transferred overnight to GeneBind 45 nylon membrane (Pharmacia LKB, Piscataway, NJ) using standard methods. Kingston, R.E., in Current Protocols in Molecular Biology, (F.M. Ausubel, R. Brent, R.E. Kingston, D.D. Moore, J.A. Smith, J.G. Seidman and K. Strahl, eds.), John Wiley and Sons, NY. RNA was UV- crosslinked to the membrane. Double-stranded 32 P-labeled probes were synthesized using the Prime a Gene labeling kit (Promega, Madison WI) . The ras probe was a Sall-Nhel fragment of a cDNA clone of the activated (mutant) H-ras mRNA having a GGC-to-GTC mutation at codon-12. The control probe was G3PDH. Blots were prehybridized for 15 minutes at 68 °C with the QuickHyb hybridization solution (Stratagene, La Jolla, CA) . The heat- denatured radioactive probe (2.5 x 10 s counts/2 ml hybridization solution) mixed with 100 μl of 10 mg/ml salmon sperm DNA was added and the membrane was hybridized for 1 hour at 68 °C. The blots were washed twice for 15 minutes at room temperature in 2x SSC/0.1% SDS and once for 30 minutes at 60 °C with 0.1XSSC/0.1%SDS. Blots were autoradiographed and the intensity of signal was quantitated using an ImageQuant Phosphorlmager (Molecular Dynamics, Sunnyvale, CA) . Northern blots were first hybridized with the ras probe, then stripped by boiling for 15 minutes in 0.Ix SSC/0.1%SDS and rehybridized with the control G3PDH probe to check for correct sample loading. The MMI-containing oligomers, compound ID No.s 9502, 9503 and 9504, identified in previous Examples above, had IC 50 s of approximately 100 nM, 90 nM and 120 nM, respectively. All were more active in this assay than a known-active phosphorothioate oligonucleotide of the same sequence that was used as the test standard. This standard phosphorothioate oligonucleotide had C50 of approximately 150 nM. Those skilled in the art will appreciate that numerous changes and modifications may be made to the preferred embodiments of the invention and that such changes and modifications may be made without departing from the spirit of the invention. It is therefore intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the invention.

Claims: WHAT IS CLAIMED IS: 1. A process for forming covalent linkages, comprising the steps of: (a) providing a support-bound synthon having structure: and (b) contacting said support-bound synthon with a solution-phase synthon having structure: said contacting being for a time and under reaction conditions effective to form a covalent linkage having structure CH=N-R A -CH 2 , CH 2 -CH=N-R A , CH 2 -R A -N=CH, or R A -N=CH- CH 2 ; wherein: Z- L and Y 2 are selected such that (i) Z 1 is C(0)H and Y 2 is CH 2 R A NH 2 ; or (ii) Z is CH 2 R A NH 2 and Y 2 is C(0)H; or (iii) Z x is CH 2 C(0)H and Y 2 is R A NH 2 ; or (iv) Zi is R A NH 2 and Y 2 is CH 2 C(0)H; each R A is, independently, 0 or NR 2 ; Y 1 is OH, OR HP , CH 2 OH, or CH 2 OR HP where R HP is a hydroxyl protecting group; (P) is a solid support; each L c is, independently, a covalent linkage having structure CH=N-R A -CH 2 , CH 2 -CH=N-R A , CH 2 -R A -N=CH, R A -N=CH-CH 2 , 0- P(0) 2 0-CH 2 , or O-P(S) (0)0-CH 2 ; n is 0-200; each R 2 is, independently, H; alkyl or substituted alkyl having 1 to about 10 carbon atoms; alkenyl or substituted alkenyl having 2 to about 10 carbon atoms; alkynyl or substituted alkynyl having 2 to about 10 carbon atoms; alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl having 7 to about 14 carbon atoms; alicyclic; heterocyclic; a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide; each B x is, independently, a nucleosidic base; each Q is, independently, 0, S, CH 2 , CHF or CF 2 ; and each X is, independently, H; OH; alkyl or substituted alkyl having 1 to about 10 carbon atoms; alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl having 7 to about 14 carbon atoms; F; Cl; Br; CN; CF 3 ; OCF 3 ; OCN; O-alkyl; S-alkyl; N-alkyl; O-alkenyl; S-alkenyl; N-alkenyl; SOCH 3 ; S0 2 CH 3 ; ON0 2 ; N0 2 ; N 3 ; NH 2 ; heterocycloalkyl; heterocycloalkaryl; aminoalkylamino; polyalkylamino or substituted silyl; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide. 2. The process of claim 1 wherein R A is 0. 3. The process of claim 1 wherein R A is NH or NCH 3 . 4. The process of claim 1 wherein Z x is C(0)H and Y 2 is CH 2 R A NH 2 . The process of claim 1 wherein Z x is CH 2 R A NH 2 and Y 2 is C(0)H. 6. The process of claim 1 wherein Z τ is CH 2 C(0)H and Y 2 is R A NH 2 . 7. The process of claim 1 wherein is R A NH 2 and Y 2 is CH 2 C(0)H. 8. The process of claim 1 wherein said support bound synthon is prepared by contacting a synthon having structure: wherein Y 2 is CH 2 R A - (phthalimido) or R A - (phthalimido) with hydrazine, methylhydrazine, or a combination thereof. 9. The process of claim 1 further comprising reducing said covalent linkage to form a reduced linkage having structure O^-NR^ A -CH a , CH^CH S -NR^R^ CH^R A -NR^O^, or R A -NR X - CH 2 -CH 2 wherein each R ± is, independently, H; alkyl or substituted alkyl having 1 to about 10 carbon atoms; alkenyl or substituted alkenyl having 2 to about 10 carbon atoms; alkynyl or substituted alkynyl having 2 to about 10 carbon atoms; alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl having 7 to about 14 carbon atoms; alicyclic; heterocyclic; a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide. 10. The process of claim 9 wherein Z x is C(0)H and Y 2 is CH 2 R A NH 2 . 11. The process of claim 9 wherein R A is 0. 12. The process of claim 9 wherein Z is CH 2 C(0)H and Y 2 is R A NH 2 . 13. The process of claim 9 further comprising alkylating a free amine group in said reduced linkage. 14. The process of claim 13 further comprising cleaving the product of said claim from said support. 15. The process of claim 1 further comprising cleaving the product of said claim from said support. 16. The process of claim 14 further comprising removing said hydroxyl protecting group from the product of said claim. 17. The process of claim 16 further comprising contacting said product in the presence of acid with a 2'- cyanoethylphosphpramidite nucleotide or a 2' -terminal cyanoethylphosphoramidite oligonucleotide to form a phosphite- linked structure. 18. The process of claim 17 further comprising oxidizing said phosphite linkage structure and hydrolyzing said cyanoethyl group. 19. The process of claim 1 further comprising removing said hydroxyl protecting group from the product of said claim. 20. A compound having structure: wherein: Z j. is C(0)H, CH 2 C(0)H, CH 2 R A NH 2 , or R A NH 2 ; R A is O or NR 2 ; Y x is OH, OR HP , CH 2 OH, or CH 2 OR HP where R HP is a hydroxyl protecting group; R 2 is H; alkyl or substituted alkyl having 1 to about 10 carbon atoms; alkenyl or substituted alkenyl having 2 to about 10 carbon atoms; alkynyl or substituted alkynyl having 2 to about 10 carbon atoms; alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl having 7 to about 14 carbon atoms; alicyclic; heterocyclic; a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacody¬ namic properties of an oligonucleotide; B x is a nucleosidic base; Q is 0, S, CH 2 , CHF or CF 2 ; and X x is H; OH; alkyl or substituted alkyl having 1 to about 10 carbon atoms; alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl having 7 to about 14 carbon atoms; F; Cl; Br; CN; CF 3 ; 0CF 3 ; OCN; O-alkyl; S-alkyl; N-alkyl; O-alkenyl; S-alkenyl; N-alkenyl; S0CH 3 ; S0 2 CH 3 ; ON0 2 ; N0 2 ; N 3 ; NH 2 ; heterocycloalkyl; heterocycloalkaryl; aminoalkylamino; polyalkylamino or substituted silyl; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide. 21. The compound of claim 20 wherein R A is O. 22. The compound of claim 20 wherein R A is NH. 23. The compound of claim 20 wherein Z is C(0)H or CH 2 C(0)H. 24 . The compound of claim 20 wherein Z x is CH 2 R A NH 2 or R A H 2 , 25. The compound of claim 20 wherein R HP is phthalimido, fluorenylmethoxycarbonyl, t-butyldimethylsilyl, or t- butyldiphenylsilyl. 26. A compound having structure: wherein : Y 2 is C (0) H , CH 2 C (0) H, CH 2 R A NH 2 , or R A NH 2 ; Z 2 is OH, 0R HP , CH 2 0H, or CH 2 0R HP ; n is 0 - 200 ; (P) is a solid support; each L c is, independently, a covalent linkage having structure CH=N-R A -CH 2 , CH 2 -CH=N-R A , CH 2 -R A -N=CH, R A -N=CH-CH 2 , CH 2 - NR^R A -CH S , CH s -CHz-NRi-R A , CH^R A -NR^O^, R A -NR- L -CT^-CH^ 0-P(0) 2 0- CH 2 , or O-P(S) (0)0-CH 2 ; each R A is, independently, O or NR 2 ; each R x and R 2 is, independently, H; alkyl or substituted alkyl having 1 to about 10 carbon atoms; alkenyl or substituted alkenyl having 2 to about 10 carbon atoms; alkynyl or substituted alkynyl having 2 to about 10 carbon atoms; alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl having 7 to about 14 carbon atoms; alicyclic; heterocyclic; a reporter molecule; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide; each B x is, independently, a nucleosidic base; each Q is, independently, 0, S, CH 2 , CHF or CF 2 ; and each X is, independently, H; OH; alkyl or substituted alkyl having 1 to about 10 carbon atoms; alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl having 7 to about 14 carbon atoms; F; Cl; Br; CN; CF 3 ; OCF 3 ; OCN; O-alkyl; S-alkyl; N-alkyl; O-alkenyl; S-alkenyl; N-alkenyl; SOCH 3 ; S0 2 CH 3 ; ON0 2 ; N0 2 ; N 3 ; NH 2 ; heterocycloalkyl; heterocycloalkaryl; aminoalkylamino; polyalkylamino or substituted silyl; an RNA cleaving group; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide. 27. The compound of claim 26 wherein R A is 0. 28. The compound of claim 26 wherein Y 2 is CH 2 R A NH 2 or R A NH 2 . 29. The compound of claim 26 wherein L c is CH=N-R A -CH 2 , CH 2 -CH=N-R A , CH 2 -R A -N=CH, or R A -N=CH-CH 2 . 30. The compound of claim 26 wherein L c is CH^NR- L -R A -CH ; ,, 31. The compound of claim 30 wherein R is H. 32. The compound of claim 30 wherein R x is CH 3 .

Inventors: COCK PHILLIP DAN, MORVAN FRANCOIS, SANGHVI YOGESH S, COCK, PHILLIP, DAN, MORVAN, FRANCOIS, SANGHVI, YOGESH, S.
Applicants: COCK PHILLIP DAN, ISIS PHARMACEUTICALS INC, MORVAN FRANCOIS, SANGHVI YOGESH S, COCK, PHILLIP, DAN, ISIS PHARMACEUTICALS, INC., MORVAN, FRANCOIS, SANGHVI, YOGESH, S.
Application year: 1994
Main classification: C07H1
IPC codes: C07H19, C07H21